Pyridopyrimidinone inhibitors of pi3kalpha

ABSTRACT

The invention is directed to Compounds of Formula I and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

The Applicants claim priority under 35 U.S.C. 119(e) to copendingProvisional Applications No. 60/724,571 filed on Oct. 7, 2005 and No.60/743,719 filed on Mar. 23, 2006, the disclosures of which areincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of protein kinases and inhibitorsthereof. In particular, the invention relates to inhibitors ofphosphatidylinositol 3-kinase (PI3K) signaling pathways, and methods oftheir use.

2. Summary of the Related Art

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors havebeen used clinically in the treatment of a wide variety of diseases,such as cancer and chronic inflammatory diseases, including diabetes andstroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001).

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharmaceutical Research,17(11):1345-1353 (2000). Viral infections and the conditions relatedthereto have also been associated with the regulation of proteinkinases. Park et al. Cell 101 (7), 777-787 (2000).

Phosphatidylinositol 3-kinase (PI3Kα), a dual specificity proteinkinase, is composed of an 85 kDa regulatory subunit and a 110 kDacatalytic subunit. The protein encoded by this gene represents thecatalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P andPtdIns(4,5)P2. PTEN, a tumor suppressor which inhibits cell growththrough multiple mechanisms, can dephosphorylate PIP3, the major productof PIK3CA. PIP3, in turn, is required for translocation of proteinkinase B (AKT1, PKB) to the cell membrane, where it is phosphorylatedand activated by upstream kinases. The effect of PTEN on cell death ismediated through the PIK3CA/AKT1 pathway.

PI3Kα has been implicated in the control of cytoskeletal reorganization,apoptosis, vesicular trafficking, proliferation and differentiationprocesses. Increased copy number and expression of PIK3CA is associatedwith a number of malignancies such as ovarian cancer (Campbell et al.,Cancer Res 2004, 64, 7678-7681; Levine et al., Clin Cancer Res 2005, 11,2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., GynecolOncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al.Cancer Biol Ther 2004, 3, 772-775; Levine, et al., supra; Li et al.,Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005,65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224),colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al.Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. CancerRes. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., Int JCancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee etal., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee etal., id.), small and non-small cell lung cancer (Tang et al., LungCancer 2006, 51, 181-191; Massion et al., Am J Respir Crit Care Med2004, 170, 1088-1094), thyroid carcinoma (Wu et al., J Clin EndocrinolMetab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobertet al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML)(Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas(Hartmann et al. Acta Neuropatliol (Berl) 2005, 109, 639-642; Samuels etal., supra).

In view of the important role of PI3Kα in biological processes anddisease states, inhibitors of this protein kinase are desirable.

SUMMARY OF THE INVENTION

The following only summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. All references cited inthis specification are hereby incorporated by reference in theirentirety. In the event of a discrepancy between the express disclosureof this specification and the references incorporated by reference, theexpress disclosure of this specification shall control.

The invention provides compounds that inhibit, regulate, and/or modulatePI3K that are useful in the treatment of hyperproliferative diseases,such as cancer, in mammals. This invention also provides methods ofmaking the compound, methods of using such compounds in the treatment ofhyperproliferative diseases in mammals, especially humans, and topharmaceutical compositions containing such compounds.

A first aspect of the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R¹ is hydrogen, optionally substituted alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heterocycloalkyl, optionally substituted    heterocycloalkylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   X is —NR³—;-   R³ hydrogen;-   R⁴ is optionally substituted alkyl;-   R⁵ is hydrogen; and-   R⁶ is acyl and R² is R^(2a) where R^(2a) is aryl, arylalkyl,    cycloalkyl, cycloalkylalkyl, or heterocycloalkyl, where the aryl,    cycloalkyl, and heterocycloalkyl, either alone or as part of another    group within R^(2a), are optionally substituted with 1, 2, 3, 4, or    5 R⁸ groups; or-   R⁶ is phenyl or heteroaryl where the phenyl and heteroaryl are    optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups; and R² is    R^(2b) where R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,    heterocycloalkyl, or heterocycloalkylalkyl, and where the aryl,    cycloalkyl, and heterocycloalkyl, either alone or as part of another    group within R^(2b), are optionally substituted with 1, 2, 3, 4, or    5 R⁸ groups;-   each R⁸, when present, is independently hydroxy, halo, alkyl,    haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxycarbonyl, amino,    alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl,    dialkylaminoalkyl, aminoalkyloxy, alkylaminoalkyloxy,    dialkylaminoalkyloxy, alkoxyalkylaminoalkyl, heterocycloalkyl,    heterocycloalkylalkyl, heterocycloalkylalkyloxy, cycloalkyl,    cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl and    where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each    either alone or as part of another group within R⁸, are    independently optionally substituted with 1, 2, 3, or 4 groups    selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy,    amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, and    arylalkyl; and-   each R⁹, when present, is independently halo, alkyl, haloalkyl,    alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxyalkyl,    carboxyalkyl, cyano, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl,    arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the    cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either    alone or as part of another group within R⁹, are independently    optionally substituted with 1, 2, 3, or 4 groups selected from halo,    alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino,    and dialkylamino.

A second aspect of the invention provides a compound of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R¹ is hydrogen, optionally substituted alkyl, optionally substituted    C₃-C₇ cycloalkyl, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted heterocycloalkyl,    optionally substituted heterocycloalkylalkyl, optionally substituted    heteroaryl or optionally substituted heteroarylalkyl;-   X is S, SO₂, or —NR³—;-   R² is hydrogen, haloalkyl, optionally substituted alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, optionally substituted    heterocycloalkyl, optionally substituted heterocycloalkylalkyl,    optionally substituted heterocycloalkyl-aryl- or optionally    substituted heteroaryl; R² is optionally further substituted with    one or more R⁸ groups;-   R³, R^(3a), and R^(3b) are independently hydrogen, optionally    substituted alkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted aryl, optionally substituted heterocycloalkyl    or optionally substituted heteroaryl;-   R⁴ is hydrogen, halo, haloalkyl, haloalkoxy, —NR^(3a)—, optionally    substituted alkyl, optionally substituted C₁-C₆ alkoxy, optionally    substituted C₁-C₆ alkoxyalkyl, optionally substituted aminoalkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted    aryl, or optionally substituted heteroaryl;-   R⁵ is hydrogen, halo, haloalkyl, haloalkoxy, optionally substituted    C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, optionally    substituted C₁-C₆ alkoxyalkyl, optionally substituted aminoalkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted    aryl, optionally substituted aryl C₁-C₆ alkyl or optionally    substituted heteroaryl; and-   R⁶ is hydrogen, halo, haloalkyl, haloalkoxy, —NR^(3b)—, optionally    substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy,    optionally substituted C₁-C₆ alkoxyalkyl, optionally substituted    acyl, optionally substituted aminoalkyl, optionally substituted    C₃-C₇ cycloalkyl, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted heterocycloalkyl, or    optionally substituted heteroaryl; substitutable R⁶ groups are    optionally further substituted with 1, 2, 3, 4, or 5 R⁹ groups;-   each R⁸, when present, is independently hydroxy, halo, haloalkyl,    haloalkoxy, optionally substituted alkyl, optionally substituted    C₁-C₆ alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ alkoxyalkylaminoalkyl, C₁-C₆    alkylcarboxyheterocycloalkyl, oxy C₁-C₆alkylheterocycloalkyl,    optionally substituted aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted aryl    C₁-C₆ alkyl, optionally substituted heterocycloalkyl, optionally    substituted heterocycloalkylalkyl, optionally substituted heteroaryl    or optionally substituted heteroarylalkyl;-   each R⁹, when present, is independently halo, haloalkyl, haloalkoxy,    optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆    alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ carboxyalkyl, optionally substituted    alkoxycarbonyl, optionally substituted aminoalkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted aryl C₁-C₆ alkyl, optionally substituted    aryloxy, optionally substituted heterocycloalkyl, or optionally    substituted heteroaryl.

In a third aspect, the invention is directed to a pharmaceuticalcomposition which comprises a compound of Formula I or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, excipient, or diluent.

In a fourth aspect, the invention comprises a method of inhibiting PI3K,comprising contacting a cell with a compound of Formula I or II or apharmaceutically acceptable salt or solvate thereof, or with apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I or II and a pharmaceutically acceptablecarrier, excipient, or diluent.

In a fifth aspect of the invention is a method of inhibiting the in vivoactivity of PI3Kα, the method comprising administering to a patient aneffective PI3Kα-inhibiting-inhibiting amount of a compound of Formula Ior II, or a pharmaceutically acceptable salt, solvate, or pharmaceuticalcomposition thereof.

In a sixth aspect, the Invention provides a method for treating adisease, disorder, or syndrome which method comprises administering to apatient a therapeutically effective amount of a compound of Formula I orII or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I or II and a pharmaceutically acceptablecarrier, excipient, or diluent.

A seventh aspect of the invention is directed to a process of preparinga compound of Formula I, comprising:

(a) reacting an intermediate of formula 7(a):

-   -   where R⁶ is phenyl or heteroaryl each optionally substituted        with 1, 2, 3, 4, or 5 R⁹ groups (as defined in the Summary of        the Invention) and R¹ and R⁴ are as defined in the Summary of        the Invention; with an intermediate of formula R^(2b)NH₂ (where        R^(2b) is as defined in the Summary of the Invention) to yield a        Compound of Formula I(a):

(b) reacting an intermediate of formula 26:

where R⁶ is phenyl or heteroaryl each optionally substituted with 1, 2,3, 4, or 5 R⁹ groups (as defined in the Summary of the Invention) and R¹and R⁴ are as defined in the Summary of the Invention; with anintermediate of formula R^(2b)X where X is halo, for example iodo, toyield a Compound of Formula I(a); or

(c) reacting an intermediate of formula 27:

-   -   where R¹, R^(2a), and R⁴ are as defined in the Summary of the        Invention; with tributyl-1-ethylvinyltin to yield a Compound of        Formula I(b):

(d) optionally further resolving individual isomers; and

(e) optionally further modifying one of the R¹, R^(2a), R^(2b), R⁴, andR⁶ groups.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl br broad ° C. degrees Celsius c- cycloCBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DCM dichloromethane DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dppf1,1′-bis(diphenylphosphano)ferrocene EI Electron Impact ionization ggram(s) h or hr hour(s) HPLC high pressure liquid chromatography Lliter(s) M molar or molarity m Multiplet mg milligram(s) MHz megahertz(frequency) Min minute(s) mL milliliter(s) μL microliter(s) μMMicromole(s) or micromolar mM Millimolar mmol millimole(s) mol mole(s)MS mass spectral analysis N normal or normality nM Nanomolar NMR nuclearmagnetic resonance spectroscopy q Quartet RT Room temperature s Singlett or tr Triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thinlayer chromatography

The symbol “—” means a single bond,

means a double bond,

means a triple bond,

means a single or double bond. The symbol

refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z-, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the

symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “Z” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Acyl” means a —C(O)R radical where R is optionally substituted alkyl,optionally substituted alkenyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl, as defined herein, e.g., acetyl,trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.

“Acylamino” means a —NRR′ radical where R is hydrogen, hydroxy, alkyl,or alkoxy and R′ is acyl, as defined herein.

“Acyloxy” means an —OR radical where R is acyl, as defined herein, e.g.cyanomethylcarbonyloxy, and the like.

“Administration” and variants thereof (e.g., “administering” a compound)in reference to a compound of the invention means introducing thecompound or a prodrug of the compound into the system of the animal inneed of treatment. When a compound of the invention or prodrug thereofis provided in combination with one or more other active agents (e.g.,surgery, radiation, and chemotherapy, etc.), “administration” and itsvariants are each understood to include concurrent and sequentialintroduction of the compound or prodrug thereof and other agents.

“Alkenyl” means a means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to 6 carbon atoms which radical contains at least one double bond,e.g., ethenyl, propenyl, 1-but-3-enyl, and 1-pent-3-enyl, and the like.

“Alkoxy” means an —OR group where R is alkyl group as defined herein.Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted withat least one, specifically one, two, or three, alkoxy groups as definedherein. Representative examples include methoxymethyl and the like.

“Alkoxyalkylamino” means an —NRR′ group where R is hydrogen, alkyl, oralkoxyalkyl and R′ is alkoxyalkyl, as defined herein.

“Alkoxyalkylaminoalkyl” means an alkyl group substituted with at leastone, specifically one or two, alkoxyalkylamino group(s), as definedherein.

“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as definedherein.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like.

“Alkylamino” means an —NHR group where R is alkyl, as defined herein.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminoalkyloxy” means an —OR group where R is alkylaminoalkyl, asdefined herein.

“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as definedherein.

“Alkynyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three to 6carbon atoms which radical contains at least one triple bond, e.g.,ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

“Amino” means —NH₂.

“Aminoalkyl” means an alkyl group substituted with at least one,specifically one, two or three, amino groups.

“Aminoalkyloxy” means an —OR group where R is aminoalkyl, as definedherein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylalkyl” means an alkyl radical, as defined herein, substituted withone or two aryl groups, as defined herein, e.g., benzyl and phenethyl,and the like.

“Aryloxy” means an —OR group where R is aryl, as defined herein.

“Carboxyalkyl” means an alkyl group, as defined herein, substituted withat least one, specifically one or two, —C(O)OH group(s).

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), monovalent hydrocarbon radicalof three to ten carbon ring atoms. Fused bicyclic hydrocarbon radicalincludes bridged ring systems. Unless stated otherwise, the valency ofthe group may be located on any atom of any ring within the radical,valency rules permitting. One or two ring carbon atoms may be replacedby a —C(O)—, —C(S)—, or —C(═NH)— group. More specifically, the termcycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.

“Cycloalkylalkyl” means an alkyl group substituted with at least one,specifically one or two, cycloalkyl group(s) as defined herein.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedherein, or an N-oxide derivative, or a protected derivative thereof,e.g., dimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or twodialkylamino groups, as defined herein.

“Dialkylaminoalkyloxy” means an —OR group where R is dialkylaminoalkyl,as defined herein. Representative examples include2-(N,N-diethylamino)-ethyloxy, and the like.

“Fused-polycyclic” or “fused ring system” means a polycyclic ring systemthat contains bridged or fused rings; that is, where two rings have morethan one shared atom in their ring structures. In this application,fused-polycyclics and fused ring systems are not necessarily allaromatic ring systems. Typically, but not necessarily, fused-polycyclicsshare a vicinal set of atoms, for example naphthalene or1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic. In some examples, asappreciated by one of ordinary skill in the art, two adjacent groups onan aromatic system may be fused together to form a ring structure. Thefused ring structure may contain heteroatoms and may be optionallysubstituted with one or more groups. It should additionally be notedthat saturated carbons of such fused groups (i.e. saturated ringstructures) can contain two substitution groups.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as definedherein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Haloalkyl” mean an alkyl group substituted with one or more halogens,specifically one to five halo atoms, e.g., trifluoromethyl,2-chloroethyl, and 2,2-difluoroethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more,specifically one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R^(x))—, andthe remaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Fused bicyclic radical includes bridged ring systems.Unless stated otherwise, the valency may be located on any atom of anyring of the heteroaryl group, valency rules permitting. When the pointof valency is located on the nitrogen, R^(x) is absent. Morespecifically, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl,imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl(including, for example, 2,3-dihydro-1H-indol-2-yl or2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl,isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl,cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl,phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl,tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Heteroarylalkyl” means an alkyl group, as defined herein, substitutedwith at least one, specifically one or two heteroaryl group(s), asdefined herein.

“Heteroatom” refers to O, S, N, or P.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 8 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more, specificallyone, two, three, or four ring heteroatoms independently selected from O,S(O)_(n) (n is 0, 1, or 2), N, N(R^(y)) (where R^(y) is hydrogen, alkyl,hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms beingcarbon. One or two ring carbon atoms may be replaced by a —C(O)—,—C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ringsystems. Unless otherwise stated, the valency of the group may belocated on any atom of any ring within the radical, valency rulespermitting. When the point of valency is located on a nitrogen atom,R^(y) is absent. More specifically the term heterocycloalkyl includes,but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl,2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl,piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl,thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl,quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and thederivatives thereof and N-oxide or a protected derivative thereof.

“Heterocycloalkylalkyl” means an alkyl radical, as defined herein,substituted with one or two heterocycloalkyl groups, as defined herein,e.g., morpholinylmethyl, N-pyrrolidinylethyl, and3-(N-azetidinyl)propyl, and the like.

“Heterocycloalkylalkyloxy means an —OR group where R isheterocycloalkylalkyl, as defined herein.

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” optional substitution may occuron both the “C₁₋₈ alkyl” portion and the “aryl” portion of the moleculemay or may not be substituted. A list of exemplary optionalsubstitutions is presented below in the definition of “substituted.”

“Optionally substituted alkoxy” means an —OR group where R is optionallysubstituted alkyl, as defined herein.

“Optionally substituted alkyl” means an alkyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, orcyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, alkyl, optionallysubstituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted alkenyl” means an alkyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, orcyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, alkyl, optionallysubstituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted amino” refers to the group —N(H)R or —N(R)Rwhere each R is independently selected from the group: optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substitutedheteroaryl, acyl, carboxy, alkoxycarbonyl, —S(O)₂-(optionallysubstituted alkyl), —S(O)₂-optionally substituted aryl),—S(O)₂-(optionally substituted heterocycloalkyl), —S(O)₂-(optionallysubstituted heteroaryl), and —S(O)₂-(optionally substituted heteroaryl).For example, “optionally substituted amino” includes diethylamino,methylsulfonylamino, and furanyl-oxy-sulfonamino.

“Optionally substituted aminoalkyl” means an alkyl group, as definedherein, substituted with at least one, specifically one or two,optionally substituted amino group(s), as defined herein.

“Optionally substituted aryl” means an aryl group, as defined herein,optionally substituted with one, two, or three substituentsindependently selected from acyl, acylamino, acyloxy, optionallysubstituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy,halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino,dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “aryl”, the alkyl and alkenyl, either aloneor as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted arylalkyl” means an alkyl group, as definedherein, substituted with optionally substituted aryl, as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl group, as definedherein, substituted with one, two, or three groups independentlyselected from acyl, acyloxy, acylamino, optionally substituted alkyl,optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro,alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,carboxy, and cyano. Within the above optional substitutents on“cycloalkyl”, the alkyl and alkenyl, either alone or as part of anothersubstituent on the cycloalkyl ring, are independently optionallysubstituted with one, two, three, four, or five halo, e.g. haloalkyl,haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl.

“Optionally substituted cycloalkylalkyl” means an alkyl groupsubstituted with at least one, specifically one or two, optionallysubstituted cycloalkyl groups, as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group optionallysubstituted with one, two, or three substituents independently selectedfrom acyl, acylamino, acyloxy, optionally substituted alkyl, optionallysubstituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl,alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano,alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within theoptional substituents on “heteroaryl”, the alkyl and alkenyl, eitheralone or as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted heteroarylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heteroaryl group(s), as defined herein.

“Optionally substituted heterocycloalkyl” means a heterocycloalkylgroup, as defined herein, optionally substituted with one, two, or threesubstituents independently selected from acyl, acylamino, acyloxy,optionally substituted alkyl, optionally substituted alkenyl, alkoxy,alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino,alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “heterocycloalkyl”, the alkyl and alkenyl,either alone or as part of another group (including, for example, thealkyl in alkoxycarbonyl), are independently optionally substituted withone, two, three, four, or five halo.

“Optionally substituted heterocycloalkylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heterocycloalkyl group(s) as defined herein.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a specific embodiment the patient is a mammal, and in amore specific embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastorna multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Specific salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)the alkyl group is a straight or branched chain. Acceptable esters alsoinclude cycloalkyl esters and arylalkyl esters such as, but not limitedto benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art.

EMBODIMENTS OF THE INVENTION

One embodiment (A) of the Invention is directed to a Compound of FormulaI where R¹ is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl. Specifically, R¹ is hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted arylalkyl, optionally substituted heterocycloalkyl, oroptionally substituted heterocycloalkylalkyl. More specifically, R¹ ishydrogen, alkyl, alkyl substituted with one or two hydroxy, alkylsubstituted with alkoxy, cycloalkyl, arylalkyl, heterocyloalkyl, orheterocycloalkylalkyl. Even more specifically, R¹ is hydrogen, methyl,ethyl, propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl,2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-isopropoxypropyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl,tetrahydrofuranyl, tetrahydropyranyl, or 2-piperidin-1-ylethyl.

In a more specific embodiment of A, an even more specific embodiment isa Compound of Formula I where R¹ is ethyl, isopropyl, cyclopentyl,tetrahydrofuranyl, or tetrahydropyranyl. Yet even more specifically, R¹is ethyl, isopropyl, or cyclopentyl.

Another embodiment (B) of the Invention is directed to a Compound ofFormula I where R⁴ is optionally substituted alkyl. Specifically, R⁴ ismethyl or ethyl. More specifically, R⁴ is methyl.

Another embodiment (C) of the Invention is directed to a Compound ofFormula I where R⁶ is acyl and R^(2a) is aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, or heterocycloalkyl, where the aryl, cycloalkyl, andheterocycloalkyl, either alone or as part of another group withinR^(2a), are optionally substituted with 1, 2, 3, 4, or 5 R⁸ groups. Morespecifically, R⁶ is alkylcarbonyl. Even more specifically, R⁶ is acetyl.

A more specific embodiment of C is directed to a Compound of Formula Iwhere R⁶ is acyl and R^(2a) is aryl where the aryl is optionallysubstituted with 1, 2, 3, 4, or 5 R⁸ groups. More specifically R^(2a) isphenyl optionally substituted with 1, 2, 3, 4, or 5 R⁸ groups. Even morespecifically, R^(2a) is phenyl optionally substituted with one R⁸ whereR⁸, when present, is heterocycloalkyl optionally substituted with alkyl,haloalkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl. Yet even morespecifically, R^(2a) is phenyl optionally substituted with one R⁸ whereR⁸, when present, is piperazinyl optionally substituted with methyl,ethyl, isopropyl, acetyl, tert-butoxycarbonyl, or benzyl.

Another embodiment (D) of the Invention is directed to a Compound ofFormula I where R⁶ is phenyl or heteroaryl where the phenyl andheteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups;and R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl, and where the aryl,cycloalkyl, and heterocycloalkyl, either alone or as part of anothergroup within R^(2b), are optionally substituted with 1, 2, 3, 4, or 5 R⁸groups. Even more specifically, R⁶ is phenyl or heteroaryl where thephenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5R⁹ groups; and R^(2b) is aryl optionally substituted with one R⁸ whereR⁸, when present, is heterocycloalkyl optionally substituted with alkyl,haloalkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl. Yet even morespecifically, R⁶ is phenyl or heteroaryl where the phenyl and heteroarylare optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups; and R^(2b)is phenyl optionally substituted with one R⁸ where R⁸, when present, ispiperazinyl optionally substituted with methyl, ethyl, isopropyl,acetyl, tert-butoxycarbonyl, or benzyl.

Another embodiment (E) of the Invention is directed to a Compound ofFormula I where R⁶ is phenyl optionally substituted with 1, 2, 3, 4, or5 R⁹ groups; and R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl, and where the aryl,cycloalkyl, and heterocycloalkyl, either alone or as part of anothergroup within R^(2b), are optionally substituted with 1, 2, 3, 4, or 5 R⁸groups. Specifically, R⁶ is phenyl optionally substituted with one ortwo R⁹ groups where each R⁹, when present, is independently halo,alkoxy, or haloalkyl. More specifically, R⁶ is phenyl, fluorophenyl,dihalophenyl, methoxyphenyl, dimethoxyphenyl, chlorophenyl,dichlorophenyl, or haloalkylphenyl. More specifically, R⁶ is phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl. Yet even more specifically, R⁶ is phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, or 3,5-difluorophenyl.

A more specific embodiment (E1) of Embodiment E is a Compound of FormulaI where R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; where the aryl andheterocycloalkyl, either alone or as part of another group withinR^(2b), are optionally substituted with one or two R⁸.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is aryl optionally substituted with one or two R⁸ where each R⁸, whenpresent, is independently halo, hydroxy, alkoxy, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy,dialkylaminoalkyloxy, heteroaryl, heterocycloalkyl, orheterocycloalkylalkyloxy; and where the heterocycloalkyl, either aloneor as part of heterocycloalkylalkyloxy, is optionally substituted withalkyl, alkoxycarbonyl, or arylalkyl.

More specifically, R^(2b) is phenyl, fluorophenyl, hydroxyphenyl,methoxyphenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl,ethylaminophenyl, diethylaminophenyl, methoxycarbonylphenyl,[(2-aminoethyl)-oxy]-phenyl, [(2-alkylamino-ethyl)-oxy]-phenyl,[(2-dialkylamino-ethyl)-oxy]-phenyl, imidazolylphenyl,morpholinylphenyl, piperazinylphenyl, (N-alkyl-piperazinyl)-phenyl,(N-alkoxycarbonyl-piperazinyl)-phenyl, (N-benzylpiperazinyl)-phenyl,(morpholinylalkyloxy)-phenyl, (piperidinylalkyloxy)-phenyl,(piperazinylalkyloxy)-phenyl, (N-alkyl-piperazinylalkyloxy)-phenyl, or(N-benzylpiperazinylalkyloxy)-phenyl.

Even more specifically, R^(2b) is phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-aminophenyl, 4-methylaminophenyl, 4-dimethylaminophenyl,4-ethylaminophenyl, 4-diethylaminophenyl, 3-methoxycarbonylphenyl,4-methoxycarbonylphenyl, 4-[(2-aminoethyl)-oxy]-phenyl,4-[(2-methylamino-ethyl)-oxy]-phenyl,4-[(2-dimethylamino-ethyl)-oxy]-phenyl, 4-[(2-aminoethyl)-oxy]-phenyl,4-[(2-ethylamino-ethyl)-oxy]-phenyl,4-[(2-diethylamino-ethyl)-oxy]-phenyl, 3-imidazol-1-ylphenyl,4-imidazol-1-ylphenyl, 3-imidazol-2-ylphenyl, 4-imidazol-2-ylphenyl,3-morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl, 3-piperazin-4-ylphenyl,4-piperazin-4-ylphenyl, 3-(N-methyl-piperazin-4-yl)-phenyl,4-(N-methyl-piperazin-4-yl)-phenyl, 3-(N-ethyl-piperazin-4-yl)-phenyl,4-(N-ethyl-piperazin-4-yl)-phenyl,3-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,4-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,3-(N-benzylpiperazin-4-yl)-phenyl, 4-(N-benzylpiperazin-4-yl)-phenyl,3-[2-(morpholin-4-yl)-ethyloxy]-phenyl,4-[2-(morpholin-4-yl)-ethyloxy]-phenyl,3-[2-(piperidinyl)-ethyloxy]-phenyl,4-[2-(piperidinyl)-ethyloxy]-phenyl,3-[2-(piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-methyl-piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(N-methyl-piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-ethyl-piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(N-ethyl-piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-benzyl-piperazin-4-yl)-ethyloxy]-phenyl, or4-[2-(N-benzyl-piperazin-4-yl)-ethyloxy]-phenyl.

Yet even more specifically, R^(2b) is phenyl, 2-fluorophenyl,4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-aminophenyl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,4-[(2-ethylamino-ethyl)-oxy]-phenyl,4-[(2-diethylamino-ethyl)-oxy]-phenyl, 4-imidazol-1-ylphenyl,4-morpholin-4-ylphenyl, 4-piperazin-4-ylphenyl, 4-piperazin-4-ylphenyl,4-(N-methyl-piperazin-4-yl)-phenyl, 4-(N-ethyl-piperazin-4-yl)-phenyl,4-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,4-[2-(morpholin-4-yl)-ethyloxy]-phenyl, or4-[2-(piperidinyl)-ethyloxy]-phenyl.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is heterocycloalkyl. More specifically, one of the heteroatoms in theheterocycloalkyl is nitrogen.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is arylalkyl. More specifically, R^(2b) is benzyl.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is cycloalkyl. More specifically, R^(2b) is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. Even more specifically, R^(2b) iscyclopropyl, cyclopentyl, or cyclohexyl.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is cycloalkylalkyl. More specifically, R^(2b) is cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl. Even morespecifically, R^(2b) is cyclopropylmethyl.

A more specific embodiment of E1 is a Compound of Formula I where R^(2b)is heterocycloalkylalkyl where the heterocyloalkyl is optionallysubstituted with one R⁸ where R⁸, when present, is alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl. More specifically, R^(2b) ismorpholinylalkyl, piperazinylalkyl, (N-alkyl-piperazin-4-yl)-alkyl,(N-alkoxycarbonyl-piperazin-4-yl)-alkyl, or(N-benzyl-piperazin-4-yl)-alkyl. Even more specifically, R^(2b) ismorpholin-4-ylmethyl, 2-(morpholin-4-yl)-ethyl,3-(morpholin-4-yl)-propyl, piperazin-4-ylmethyl,(N-methyl-piperazin-4-yl)-methyl, (N-ethyl-piperazin-4-yl)-methyl,2-(piperazin-4-yl)-ethyl, 2-(N-methyl-piperazin-4-yl)-ethyl,2-(N-ethyl-piperazin-4-yl)-ethyl, 3-(piperazin-4-yl)-propyl,3-(N-methyl-piperazin-4-yl)-propyl, 3-(N-ethyl-piperazin-4-yl)-propyl,(N-tert-butoxycarbonyl-piperazin-4-yl)-methyl,2-(N-tert-butoxycarbonyl-piperazin-4-yl)-ethyl,3-(N-tert-butoxycarbonyl-piperazin-4-yl)-propyl,(N-benzyl-piperazin-4-yl)-methyl, 2-(N-benzyl-piperazin-4-yl)-ethyl, or3-(N-benzyl-piperazin-4-yl)-propyl. Yet even more specifically, R^(2b)is 2-(morpholin-4-yl)-ethyl or 3-(morpholin-4-yl)-propyl.

Another embodiment (F) of the Invention is directed to a Compound ofFormula I where R⁶ is heteroaryl optionally substituted with 1, 2, 3, 4,or 5 R⁹ groups; and R^(2b) is aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and wherethe aryl, cycloalkyl, and heterocycloalkyl, either alone or as part ofanother group within R^(2b), are optionally substituted with 1, 2, 3, 4,or 5 R⁸ groups.

A more specific embodiment (F1) of embodiment F is a Compound of FormulaI where R⁶ is a 5-membered heteroaryl or a 6-membered heteroaryl.

A more specific embodiment (F2) of embodiment F is a Compound of FormulaI where R⁶ is a 6-membered heteroaryl optionally substituted with one ortwo R⁹. More specifically, R⁶ is pyridinyl, pyrazinyl, pyrimidinyl, orpyridazinyl each of which is optionally substituted with one R⁹ whereR⁹, when present, is halo; and R^(2b) is phenyl optionally substitutedwith one R⁸ where R⁸, when present, is heterocycloalkyl optionallysubstituted with alkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl.Even more specifically, R⁶ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,3-fluoropyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl; andR^(2b) is phenyl optionally substituted with one R⁸ where R⁸, whenpresent, is morpholinyl or is piperazinyl optionally substituted withmethyl, ethyl, isopropyl, acetyl, tert-butoxycarbonyl, or benzyl.

In an even more specific embodiment (F2a) of embodiment F2 is a Compoundof Formula I where R⁶ is pyrazinyl, pyrimidinyl, or pyridazinyl andR^(2b) is phenyl optionally substituted with one R⁸ where R⁸, whenpresent, is heterocycloalkyl optionally substituted with alkyl,alkylcarbonyl, alkoxycarbonyl, or arylalkyl. In yet an even morespecific embodiment, R^(2b) is phenyl optionally substituted with one R⁸where R⁸, when present, is morpholinyl or is piperazinyl optionallysubstituted with methyl, ethyl, isopropyl, acetyl, tert-butoxycarbonyl,or benzyl. Yet even more specifically, R⁶ is pyrimidin-5-yl.

A more specific embodiment (F3) of embodiment F is a Compound of FormulaI where R⁶ is 5-membered heteroaryl optionally substituted with one ortwo R⁹. Specifically R⁶ is pyrazolyl, imidazolyl, thienyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, ortetrazolyl each of which is optionally substituted with one R⁹ where R⁹,when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.More specifically, R⁶ is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl,pyrrol-3-yl, triazol-1-yl, triazol-4-yl, triazol-5-yl, tetrazol-1-yl, ortetrazol-5-yl; each of which is optionally substituted with one R⁹ whereR⁹, when present, is methyl, benzyl, cyano, phenyl,N-tert-butoxycarbonyl, or chloro. Even more specifically, R⁶ ispyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl,triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which isoptionally substituted with one R⁹ where R⁹, when present, is methyl,benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro.

A more specific embodiment (F4) of embodiment F is a Compound of FormulaI where R⁶ is thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl,pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, or thiazol-2-yl.More specifically, R⁶ is thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl,pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, or thiazol-2-yl.

A more specific embodiment (F3a) of embodiment F3 is a Compound ofFormula I where R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; where the aryl andheterocycloalkyl, either alone or as part of another group withinR^(2b), are optionally substituted with one or two R⁸.

A more specific embodiment (F3a1) of F3a is a Compound of Formula Iwhere R^(2b) is heterocycloalkyl. Specifically, R^(2b) isheterocycloalkyl where one of the heteroatoms in the heterocycloalkyl isnitrogen.

A more specific embodiment (F3a2) of F3a is a Compound of Formula Iwhere R^(2b) is R^(2b) is arylalkyl. Specifically, R^(2b) is benzyl.

A more specific embodiment (F3a3) of F3a is a Compound of Formula Iwhere R^(2b) is cycloalkyl. Specifically cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. More specifically, R^(2b) is cyclopentyl orcyclohexyl.

A more specific embodiment (F3a4) of F3a is a Compound of Formula Iwhere R^(2b) is cycloalkylalkyl. More specifically, R^(2b) iscyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, orcyclohexylmethyl. Even more specifically, R^(2b) is cyclopropylmethyl.

A more specific embodiment (F3a5) of F3a is a Compound of Formula Iwhere R^(2b) is heterocycloalkylalkyl where the heterocyloalkyl isoptionally substituted with one R⁸ where R⁸, when present, is alkyl,alkoxycarbonyl, or arylalkyl. More specifically, R^(2b) ismorpholinylalkyl, piperazinylalkyl, (N-alkyl-piperazin-4-yl)-alkyl,(N-alkoxycarbonyl-piperazin-4-yl)-alkyl, or(N-benzyl-piperazin-4-yl)-alkyl. Even more specifically, R^(2b) ismorpholin-4-ylmethyl, 2-(morpholin-4-yl)-ethyl,3-(morpholin-4-yl)-propyl, piperazin-4-ylmethyl,(N-methyl-piperazin-4-yl)-methyl, (N-ethyl-piperazin-4-yl)-methyl,2-(piperazin-4-yl)-ethyl, 2-(N-methyl-piperazin-4-yl)-ethyl,2-(N-ethyl-piperazin-4-yl)-ethyl, 3-(piperazin-4-yl)-propyl,3-(N-methyl-piperazin-4-yl)-propyl, 3-(N-ethyl-piperazin-4-yl)-propyl,(N-tert-butoxycarbonyl-piperazin-4-yl)-methyl,2-(N-tert-butoxycarbonyl-piperazin-4-yl)-ethyl,3-(N-tert-butoxycarbonyl-piperazin-4-yl)-propyl,(N-benzyl-piperazin-4-yl)-methyl, 2-(N-benzyl-piperazin-4-yl)-ethyl, or3-(N-benzyl-piperazin-4-yl)-propyl. Yet even more specifically, R^(2b)is 2-(morpholin-4-yl)-ethyl or 3-(morpholin-4-yl)-propyl.

A more specific embodiment (F3a6) of F3a is a Compound of Formula Iwhere R^(2b) is aryl optionally substituted with one or two R⁸ whereeach R⁸ is independently halo, hydroxy, alkoxy, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy,dialkylaminoalkyloxy, heteroaryl, heterocycloalkyl, orheterocycloalkylalkyloxy; and where the heterocycloalkyl, either aloneor as part of heterocycloalkylalkyloxy, is optionally substituted withalkyl, alkoxycarbonyl, or arylalkyl.

More specifically, R^(2b) is phenyl, fluorophenyl, hydroxyphenyl,methoxyphenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl,ethylaminophenyl, diethylaminophenyl, methoxycarbonylphenyl,[(2-aminoethyl)-oxy]-phenyl, [(2-alkylamino-ethyl)-oxy]-phenyl,[(2-dialkylamino-ethyl)-oxy]-phenyl, imidazolylphenyl,morpholinylphenyl, piperazinylphenyl, (N-alkyl-piperazinyl)-phenyl,(N-alkoxycarbonyl-piperazinyl)-phenyl, (N-benzylpiperazinyl)-phenyl,(morpholinylalkyloxy)-phenyl, (piperidinylalkyloxy)-phenyl,(piperazinylalkyloxy)-phenyl, (N-alkyl-piperazinylalkyloxy)-phenyl, or(N-benzylpiperazinylalkyloxy)-phenyl.

Even more specifically, R^(2b) is phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-aminophenyl, 4-methylaminophenyl, 4-dimethylaminophenyl,4-ethylaminophenyl, 4-diethylaminophenyl, 3-methoxycarbonylphenyl,4-methoxycarbonylphenyl, 4-[(2-aminoethyl)-oxy]-phenyl,4-[(2-methylamino-ethyl)-oxy]-phenyl,4-[(2-dimethylamino-ethyl)-oxy]-phenyl, 4-[(2-aminoethyl)-oxy]-phenyl,4-[(2-ethylamino-ethyl)-oxy]-phenyl,4-[(2-diethylamino-ethyl)-oxy]-phenyl, 3-imidazol-1-ylphenyl,4-imidazol-1-ylphenyl, 3-imidazol-2-ylphenyl, 4-imidazol-2-ylphenyl,3-morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl, 3-piperazin-4-ylphenyl,4-piperazin-4-ylphenyl, 3-(N-methyl-piperazin-4-yl)-phenyl,4-(N-methyl-piperazin-4-yl)-phenyl, 3-(N-ethyl-piperazin-4-yl)-phenyl,4-(N-ethyl-piperazin-4-yl)-phenyl,3-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,4-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,3-(N-benzylpiperazin-4-yl)-phenyl, 4-(N-benzylpiperazin-4-yl)-phenyl,3-[2-(morpholin-4-yl)-ethyloxy]-phenyl,4-[2-(morpholin-4-yl)-ethyloxy]-phenyl,3-[2-piperidinyl)-ethyloxy]-phenyl, 4-[2-(piperidinyl)-ethyloxy]-phenyl,3-[2-(piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-methyl-piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(N-methyl-piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-ethyl-piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(N-ethyl-piperazin-4-yl)-ethyloxy]-phenyl,3-[2-(N-benzyl-piperazin-4-yl)-ethyloxy]-phenyl, or4-[2-(N-benzyl-piperazin-4-yl)-ethyloxy]-phenyl.

Yet even more specifically, R^(2b) is phenyl, 2-fluorophenyl,4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-aminophenyl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,4-[(2-ethylamino-ethyl)-oxy]-phenyl,4-[(2-diethylamino-ethyl)-oxy]-phenyl, 4-imidazol-1-ylphenyl,4-morpholin-4-ylphenyl, 4-piperazin-4-ylphenyl, 4-piperazin-4-ylphenyl,4-(N-methyl-piperazin-4-yl)-phenyl, 4-(N-ethyl-piperazin-4-yl)-phenyl,4-(N-tert-butoxycarbonyl-piperazin-4-yl)-phenyl,4-[2-(morpholin-4-yl)-ethyloxy]-phenyl, or4-[2-(piperidinyl)-ethyloxy]-phenyl.

Another embodiment (G) of the Invention is a Compound of Formula I whereR^(2b) is phenyl, fluorophenyl, hydroxyphenyl, methoxyphenyl,aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl,diethylaminophenyl, methoxycarbonylphenyl, [(2-aminoethyl)-oxy]-phenyl,[(2-alkylamino-ethyl)-oxy]-phenyl, [(2-dialkylamino-ethyl)-oxy]-phenyl,imidazolylphenyl, morpholinylphenyl, piperazinylphenyl,(N-alkyl-piperazinyl)-phenyl, (N-alkoxycarbonyl-piperazinyl)-phenyl,(N-benzylpiperazinyl)-phenyl, (morpholinylalkyloxy)-phenyl,(piperidinylalkyloxy)-phenyl, (piperazinylalkyloxy)-phenyl,(N-alkyl-piperazinylalkyloxy)-phenyl,(N-benzylpiperazinylalkyloxy)-phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, morpholinylalkyl, piperazinylalkyl,(N-alkyl-piperazin-4-yl)-alkyl, (N-alkoxycarbonyl-piperazin-4-yl)-alkyl,or (N-benzyl-piperazin-4-yl)-alkyl.

Another embodiment (H) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R⁶ is heteroaryl optionallysubstituted with one or two R⁹ groups. Specifically, each R⁹, whenpresent, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl,or halo. Specifically, R⁶ is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl,pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl;each of which is optionally substituted with one R⁹ where R⁹, whenpresent, is methyl, benzyl, cyano, phenyl, or N-tert-butoxycarbonyl.

Another embodiment (J) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R⁶ is phenyl optionallysubstituted with one or two R⁹ groups. Specifically each R⁹, whenpresent, is independently halo, alkoxy, or haloalkyl.

Another embodiment (K) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R^(2b) is aryl substitutedwith one or two R⁸. Specifically, R^(2b) is phenyl and each R⁸ isindependently halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino,alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,heteroaryl, heterocycloalkyl, or heterocycloalkylalkyloxy and where theheterocycloalkyl in R⁸, either alone or as part ofheterocycloalkylalkyloxy, is optionally substituted with alkyl,alkoxycarbonyl, aryl, or arylalkyl. More specifically, R^(2b) is phenyland substituted with one R⁸ where R⁸ is heterocycloalkyl optionallysubstituted with alkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl.

Another embodiment (L) of the Invention is a Compound of Formula whereR¹ is alkyl or cycloalkyl; X is —NH—; R⁴ is alkyl; R⁵ is hydrogen; and

-   R⁶ is acyl; and R² is R^(2b) where R^(2a) is aryl where the aryl is    optionally substituted with one R⁸ group; or-   R⁶ is phenyl or heteroaryl where the phenyl and heteroaryl are    optionally substituted with one or two R⁹ groups; and R² is R^(2b)    where R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, or    heterocycloalkylalkyl, and where the aryl, cycloalkyl, and    heterocycloalkyl, either alone or as part of another group within    R^(2b), are optionally substituted with one or two R⁸ groups;-   each R⁸, when present, is independently halo, hydroxy, alkoxy,    amino, alkylamino, dialkylamino, alkoxycarbonyl, aminoalkyloxy,    alkylaminoalkyloxy, dialkylaminoalkyloxy, heteroaryl,    heterocycloalkyl, or heterocycloalkylalkyloxy, and where the    heterocycloalkyl, either alone or as part of another group within    R⁸, is optionally substituted with alkyl, haloalkyl, alkylcarbonyl,    alkoxycarbonyl, or arylalkyl; and-   each R⁹, when present, is independently halo, alkyl, haloalkyl,    alkoxy, aryl, arylalkyl, cyano, or alkoxycarbonyl.

Another embodiment of the Invention (M) is a Compound of Formula 1 whereR⁶ is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl,imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl,triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups.

Another embodiment (N) of the Invention is a method of treating disease,disorder, or syndrome where the disease is associated with uncontrolled,abnormal, and/or unwanted cellular activities effected directly orindirectly by PI3Kα which method comprises administering to a human inneed thereof a therapeutically effective amount of a compound of FormulaI or II or a pharmaceutically acceptable salt, solvate, orpharmaceutical composition thereof.

Another embodiment (P) of the invention is directed to a method oftreating a disease, disorder, or syndrome which method comprisesadministering to a patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula I and a pharmaceuticallyacceptable carrier, excipient, or diluent. Specifically, the disease iscancer. More specifically, the cancer is breast cancer, colon cancer,rectal cancer, endometrial cancer, gastric carcinoma, glioblastoma,hepatocellular carcinoma, small cell lung cancer, non-small cell lungcancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer,prostate carcinoma, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), or thyroid carcinoma. Even morespecifically, the cancer is ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, or glioblastomas.

Another embodiment (Q) of the Invention is directed to a method oftreating a disease, disorder, or syndrome which method comprisesadministering to a patient a therapeutically effective amount of acompound of Formula II or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula II and a pharmaceuticallyacceptable carrier, excipient, or diluent. Specifically, the disease iscancer. More specifically, the cancer is breast cancer, colorectalcancer, endometrial cancer, gastric carcinoma, glioblastoma,hepatocellular carcinoma, small cell lung cancer, non-small cell lungcancer, melanoma, ovarian cancer, endometrial cancer, cervical cancer,pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), melanoma, or thyroid carcinoma. Evenmore specifically, the cancer is breast cancer, non-small cell lungcancer, small cell lung cancer, glioblastoma, acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), prostate carcinoma, melanoma,ovarian cancer, pancreatic cancer, colorectal cancer, endometrialcancer, thyroid carcinoma, or gastric carcinoma. Yet even morespecifically, the cancer is ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, or glioblastomas.

Another aspect of the invention is a method of inhibiting proliferativeactivity in a cell, the method comprising administering to a cell or aplurality of cells an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, solvate, or prodrug thereof, orpharmaceutical composition thereof.

Another aspect of the invention is directed to employing the compoundsof the invention in a method of screening for candidate agents that bindto, for example PI3Kα. The protein is bound to a support, and a compoundof the invention is added to the assay. Alternatively, the compound ofthe invention is bound to the support and the protein is added. Classesof candidate agents among which novel binding agents may be soughtinclude specific antibodies, non-natural binding agents identified inscreens of chemical libraries, peptide analogs, etc. Of particularinterest are screening assays for candidate agents that have a lowtoxicity for human cells. A wide variety of assays may be used for thispurpose, including labeled in vitro protein-protein binding assays,electrophoretic mobility shift assays, immunoassays for protein binding,functional assays (phosphorylation assays, etc.) and the like.

The determination of the binding of the candidate agent to, for example,PI3Kα can be done in a number of ways. In one example, the candidateagent (the compound of the invention) is labeled, for example, with afluorescent or radioactive moiety and binding determined directly. Forexample, this may be done by attaching all or a portion of the PI3Kαprotein to a solid support, adding a labeled agent (for example acompound of the invention in which at least one atom has been replacedby a detectable isotope), washing off excess reagent, and determiningwhether the amount of the label is that present on the solid support.Various blocking and washing steps may be utilized as is known in theart.

The term “labeled” as used herein is meant to include both direct andindirect labeling with a compound that provides a detectable signal, forexample, radioisotope, fluorescent tag, enzyme, antibodies, particlessuch as magnetic particles, chemiluminescent tag, or specific bindingmolecules, and the like. Specific binding molecules include pairs, suchas biotin and streptavidin, digoxin and antidigoxin, and the like. Forthe specific binding members, the complementary member would normally belabeled with a molecule which provides for detection, in accordance withknown procedures, as outlined above. The label can directly orindirectly provide a detectable signal.

In some embodiments, only one of the components is labeled. For example,PI3Kα protein may be labeled at tyrosine positions using ¹²⁵I, or withfluorophores. Alternatively, more than one component may be labeled withdifferent labels; using ¹²⁵I for the proteins, for example, and afluorophor for the candidate agents.

The compounds of the invention may also be used as competitors to screenfor additional drug candidates. The terms “candidate bioactive agent” or“drug candidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. In the case where protein binding oractivity is screened, some embodiments exclude molecules already knownto bind to that particular protein. Exemplary embodiments of assaysdescribed herein include candidate agents, which do not bind the targetprotein in its endogenous native state, termed herein as “exogenous”agents. In one example, exogenous agents further exclude antibodies toPI3Kα.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules having a molecular weight of morethan about 100 and less than about 2,500 daltons. Candidate agentscomprise functional groups necessary for structural interaction withproteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl, hydroxyl, ether, orcarboxyl group, for example at least two of the functional chemicalgroups. The candidate agents often comprise carbocyclic or heterocyclicstructures and/or aromatic or polyaromatic structures substituted withone or more of the above functional groups. Candidate agents are alsofound among biomolecules including peptides, saccharides, fatty acids,steroids, purines, pyrimidines, derivatives, structural analogs, orcombinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

In one example, the binding of the candidate agent is determined throughthe use of competitive binding assays. In this example, the competitoris a binding moiety known to bind to PI3Kα, such as an antibody,peptide, binding partner, ligand, etc. Under certain circumstances,there may be competitive binding as between the candidate agent and thebinding moiety, with the binding moiety displacing the candidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to PI3Kαprotein for a time sufficient to allow binding, if present. Incubationsmay be performed at any temperature that facilitates optimal activity,typically between 4° C. and 40° C.

Incubation periods are selected for optimum activity, but may also beoptimized to facilitate rapid high throughput screening. Typicallybetween 0.1 and 1 hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In one example, the competitor is added first, followed by the candidateagent. Displacement of the competitor is an indication the candidateagent is binding to PI3Kα and thus is capable of binding to, andpotentially modulating, the activity of the PI3Kα. In this embodiment,either component can be labeled. Thus, for example, if the competitor islabeled, the presence of label in the wash solution indicatesdisplacement by the agent. Alternatively, if the candidate agent islabeled, the presence of the label on the support indicatesdisplacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound toPI3Kα with a higher affinity. Thus, if the candidate agent is labeled,the presence of the label on the support, coupled with a lack ofcompetitor binding, may indicate the candidate agent is capable ofbinding to PI3Kα.

It may be of value to identify the binding site of PI3Kα. This can bedone in a variety of ways. In one embodiment, once PI3Kα is identifiedas binding to the candidate agent, the PI3Kα is fragmented or modifiedand the assays repeated to identify the necessary components forbinding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of PI3Kα comprising the steps of combining acandidate agent with PI3Kα, as above, and determining an alteration inthe biological activity of the PI3Kα. Thus, in this embodiment, thecandidate agent should both bind to (although this may not benecessary), and alter its biological or biochemical activity as definedherein. The methods include both in vitro screening methods and in vivoscreening of cells for alterations in cell viability, morphology, andthe like.

Alternatively, differential screening may be used to identify drugcandidates that bind to native PI3Kα, but cannot bind to modified PI3Kα.

Positive controls and negative controls can be used in the assays. Forexample, all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofsamples is for a time sufficient for the binding of the agent to theprotein. Following incubation, samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples can be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents can be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which may be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,may be used. The mixture of components can be added in any order thatprovides for the requisite binding.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particularPI3Kα-ligand-ligand complexes, and their corresponding x-ray structurecoordinates can be used to reveal new structural information useful forunderstanding the biological activity of kinases as described herein. Aswell, the key structural features of the aforementioned proteins,particularly, the shape of the ligand binding site, are useful inmethods for designing or identifying selective modulators of kinases andin solving the structures of other proteins with similar features. Suchprotein-ligand complexes, having compounds of the invention as theirligand component, are an aspect of the invention.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods may be characterized by the followingaspects: a) introducing into a suitable computer program, informationdefining a ligand binding domain of a kinase in a conformation (e.g. asdefined by x-ray structure coordinates obtained from suitable x-rayquality crystals as described above) wherein the computer programcreates a model of the three dimensional structures of the ligandbinding domain, b) introducing a model of the three dimensionalstructure of a candidate agent in the computer program, c) superimposingthe model of the candidate agent on the model of the ligand bindingdomain, and d) assessing whether the candidate agent model fitsspatially into the ligand binding domain. Aspects a-d are notnecessarily carried out in the aforementioned order. Such methods mayfurther entail: performing rational drug design with the model of thethree-dimensional structure, and selecting a potential candidate agentin conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following aspects: a) creating a computer model of a kinase bindingpocket using structure coordinates obtained from suitable x-ray qualitycrystals of the kinase, b) employing computational algorithms to performa fitting operation between the test agent and the computer model of thebinding pocket, and c) analyzing the results of the fitting operation toquantify the association between the test agent and the computer modelof the binding pocket.

Representative Compounds

Representative compounds of Formula I and/or II are depicted below. Theexamples are merely illustrative and do not limit the scope of theinvention in any way. Compounds of the invention are named according tosystematic application of the nomenclature rules agreed upon by theInternational Union of Pure and Applied Chemistry (IUPAC), InternationalUnion of Biochemistry and Molecular Biology (IUBMB), and the ChemicalAbstracts Service (CAS). Names were generated using ACD/Labs namingsoftware 8.00 release, product version 8.08.

TABLE 1 Example Structure Name 1

6-bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one2

6-bromo-8-ethyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one3

6-bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one4

8-ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one5

6-bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one6

6-bromo-8-ethyl-4-methyl-2-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one7

6-bromo-8-ethyl-4-methyl-2-[(3-morpholin-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one8

6-bromo-8-ethyl-2-[(2-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one9

6-bromo-8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one10

6-bromo-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one11

6-bromo-8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one12

6-bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one13

8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one14

8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl)phenyl}amino)-6-(2-thienyl)pyridol[2,3-d]pyrimidin-7(8H)-one15

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one16

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one17

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one18

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one19

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one20

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methy1-8-(1-methylethyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one21

2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one22

8-ethyl-2-{(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one23

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one24

6-(3,5-difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one25

8-ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one26

8-ethyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one27

6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one28

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one29

6-acetyl-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one30

1,1-dimethylethyl4-{4-[(6-bromo-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]phenyl}piperazine-1-carboxylate31

6-bromo-8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one32

cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyridol[2,3-d]pyrimidin-7(8H)-one33

6-bromo-8-ethyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one34

8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one35

6-bromo-8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one36

6-bromo-8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one37

8-cyclopentyl-4-methyl-2-(phenylamino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one38

1,1-dimethylethyl4-(4-{[8-cyclopentyl-4-methyl-7-oxo-6-(1H-pyrazol-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazine-1-carboxylate39

8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one40

8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one41

2-(cyclopropylamino)-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one42

2-[(cyclopropylmethyl)amino]-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one43

8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one44

8-cyclopentyl-4-methyl-2-{[4-(methyloxy)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one45

8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one46

8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one47

8-ethy1-4-methy1-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one48

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one49

8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one50

2-[(4-aminophenyl)amino]-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one51

methyl3-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate52

methyl4-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate53

8-cyclopentyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one54

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one55

8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one56

8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one57

8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one58

8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one59

8-cyclopentyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one60

8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one61

8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one62

8-ethyl-4-methyl-2-({[4-(4-methylpiperazin-1-yl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one63

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one64

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one65

8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one66

8-cyclohexyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one67

6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one68

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one69

6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one70

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one71

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3R)-tetrahydrofuran-3-yl]pyrido[2,3-d]pyrimidin-7(8H)-one72

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3S)-tetrahydrofuran-3-yl]pyrido[2,3-d]pyrimidin-7(8H)-one73

8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one74

8-cyclopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one75

8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one76

8-cyolopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

General Administration

In one aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of PI3K according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. In certainother specific embodiments, administration is by the oral route.Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, specifically in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylalted hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts or solvates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compounds of the present invention can beadministered to a patient at dosage levels in the range of about 0.1 toabout 1,000 mg per day. For a normal human adult having a body weight ofabout 70 kilograms, a dosage in the range of about 0.01 to about 100 mgper kilogram of body weight per day is an example. The specific dosageused, however, can vary. For example, the dosage can depend on a numberof factors including the requirements of the patient, the severity ofthe condition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Representative pharmaceutical formulations containing a compound ofFormula I are described below in the Pharmaceutical CompositionExamples.

Utility

Certain compounds of this invention have been tested using the assaydescribed in Biological Example 1 and have been determined to be PI3Kinhibitors. As such compounds of Formula I are useful for treatingdiseases, particularly cancer in which PI3K activity contributes to thepathology and/or symptomatology of the disease. For example, cancer inwhich PI3K activity contributes to its pathology and/or symptomatologyinclude breast cancer, colon cancer, rectal cancer, endometrial cancer,gastric carcinoma, glioblastoma, hepatocellular carcinoma, small celllung cancer, non-small cell lung cancer, melanoma, ovarian cancer,cervical cancer, pancreatic cancer, prostate carcinoma, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), andthyroid carcinoma

Suitable in vitro assays for measuring PI3K activity and the inhibitionthereof by compounds are known in the art. For further details of an invitro assay for measuring PI3K activity see Biological Examples, Example1 infra. Following the examples disclosed herein, as well as thatdisclosed in the art, a person of ordinary skill in the art candetermine the inhibitory activity of a compound of this invention.

Assays for measurement of in vitro efficacy in treatment of cancer areknown in the art. In addition, cell-based tumor models are described inBiological Examples, Example 2, 3, and 4 infra.

Suitable in vivo models for cancer are known to those of ordinary skillin the art. For further details of in vivo models for prostateadenocarcinoma, glioblastoma, lung carcinoma, and melanoma, seeBiological Examples 5, 6, 7, 8, 9, and 10, infra.

General Synthesis

Compounds of this invention can be made by the synthetic proceduresdescribed below. The starting materials and reagents used in preparingthese compounds are either available from commercial suppliers such asAldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), orare prepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this invention can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art having referred to thisdisclosure. The starting materials and the intermediates of the reactionmay be isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure and over a temperature range from about−78° C. to about 150° C., more specifically from about 0° C. to about125° C. and more specifically at about room (or ambient) temperature,e.g., about 20° C. Unless otherwise stated (as in the case of anhydrogenation), all reactions are performed under an atmosphere ofnitrogen.

Prodrugs can be prepared by techniques known to one skilled in the art.These techniques generally modify appropriate functional groups in agiven compound. These modified functional groups regenerate originalfunctional groups by routine manipulation or in vivo. Amides and estersof the compounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms or quaternized nitrogen atoms intheir structure. Compounds of Formula I that may be prepared through thesyntheses described herein may exist as single stereoisomers, racemates,and as mixtures of enantiomers and diastereomers. The compounds may alsoexist as geometric isomers. All such single stereoisomers, racemates andmixtures thereof, and geometric isomers are intended to be within thescope of this invention. Some of the compounds of the invention mayexist as tautomers. For example, where a ketone or aldehyde is present,the molecule may exist in the enol form; where an amide is present, themolecule may exist as the imidic acid; and where an enamine is present,the molecule may exist as an imine. All such tautomers are within thescope of the invention.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom, the nitrogen atom can beconverted to an N-oxide by methods well known in the art. When compoundsof Formula I contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable “protecting group” or “protective group”. A comprehensive listof suitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1991, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula I can be prepared bymethods well known in the art.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The chemistry for the preparation of the compounds of this invention isknown to those skilled in the art. In fact, there may be more than oneprocess to prepare the compounds of the invention. For specificexamples, see M. Barvian et al. J. Med. Chem. 2000, 43, 4606-4616; S. N.VanderWei et al. J. Med. Chem. 2005, 48, 2371-2387; P. L. Toogood et al.J. Med. Chem. 2005, 48, 2388-2406; J. Kasparec et al. TetrahedronLetters 2003, 44, 4567-4570; and references cited therein. See also U.S.Pre-grant publication US2004/0009993 A1 (M. Angiolini et al.), which isincorporated herein by reference, and references cited therein. Thefollowing examples illustrate but do not limit the invention. Allreferences cited herein are incorporated by reference in their entirety.

A compound of the invention where R¹ is optionally substituted alkyl,R^(2b) is as defined in the Summary of the Invention, R⁴ is methyl orethyl, and R⁶ is phenyl or heteroaryl each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R⁹ groups (as defined in the Summaryof the Invention) can be prepared according to Scheme 1.

To a solution of commercially available 2-methyl-2-thiopseudoureasulfate in a solvent such as water is added a base such as sodiumcarbonate and an intermediate of formula 10 at room temperature. Thereaction mixture is stirred for overnight or less. After neutralizing,11 is collected through filtration and followed by drying under vacuum.11 is then treated with POCl₃ and the reaction is heated to reflux forapproximately 2 h and then concentrated under vacuum to dryness. 1 canbe used directly in the next reaction without further purification.

An intermediate of formula 2 is prepared by reacting an intermediate offormula 1 with a primary amine R¹NH₂ in a solvent such as water and withheating. 2 is then treated with iodine monochloride in a solvent such asmethanol at around 0° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form3. After completion the residue is triturated with acetone. Theintermediate 3 is then reacted in a solvent, such as DMA, with ethylacrylate in the presence of a base, such as triethylamine, and in thepresence of a catalyst, such as Pd(OAc)₂, and (+)BINAP. The reaction isheated to approximately 100° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form4. 4 is then optionally purified by column chromatography.

5 is prepared by treating 4 with DBU in the presence of a base such asDIPEA at room temperature. Then the reaction mixture is heated to refluxand reacted for approximately 15 h. After evaporation of solvent, theresidue is triturated with acetone and collected by filtration to yield5.

6 is prepared by reacting 5 with a brominating agent such as Br₂ in asolvent such as DCM at room temperature. Then the reaction mixture isstirred for approximately overnight. The resulting product is filteredand then suspended in a solvent such as DCM and treated with a base suchas triethylamine. The mixture is then washed with water and dried over adrying agent such as Na₂SO₄ to yield 6.

A Suzuki coupling is then performed using 6 reacting with a boronic acid(or ester) of formula R⁶B(OH)₂ in a solvent(s) such as a DME-H₂Omixture, in the presence of a catalyst such as Pd(dpppf) and a base suchas triethylamine at room temperature. The reaction mixture is heated toreflux for approximately 4 h. After cooling to room temperature, thereaction mixture is partitioned with water and ethyl acetate. Afterseparation, the organic layer is dried over a drying agent such asNa₂SO₄ to yield 7.

The methylthio group of 7 is then oxidized with m-CPBA in a solvent suchas DCM at room temperature allowing to stir for approximately 4 h. Afterremoval of the solvent under reduced pressure, the product is treatedwith an amine of formula R^(2b)NH₂ in a solvent such as dioxane andstirred at room temperature for approximately overnight to yield aCompound of Formula I.

Alternatively, a compound of the invention where R¹ is optionallysubstituted alkyl, R⁴ is methyl or ethyl, R⁶ is phenyl or heteroaryleach of which is optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups(as defined in the Summary of the Invention), and R^(2b) is as definedin the Summary of the Invention, can be prepared according to Scheme 2.

An intermediate of formula 9 is prepared by reacting an intermediate offormula 8 with neat POCl₃ and heating. 9 is then treated with a primaryamine R¹NH₂ in a solvent such as water or THF and triethylamine at 0° C.to form 10. After removal of the solvent under reduced pressure, theintermediate 10 is then reacted with lithium aluminum hydride in asolvent such as THF at 0° C. After quenching and aqueous workup, solventremoval provided crystalline 11 without further purification. Treatmentof 11 with manganese (II) dioxide in a solvent such as methylenechloride or chloroform at room temperature provided aldehyde 12 uponfiltration and solvent removal. A Wittig reaction with aldehyde 12 canbe employed with (carbethoxymethylene)triphenylphosphorane in refluxingTHF to provide the common intermediate 4. 4 can then be used to preparea Compound of Formula I using the procedures described in Scheme 1.

A compound of the invention where R¹ is optionally substituted alkyl, R⁴is methyl or ethyl, R⁶ is phenyl or heteroaryl each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups (as defined inthe Summary of the Invention), and R^(2b) is aryl optionally substitutedwith 1, 2, 3, 4, or 5 R⁸ groups (where R⁸ is as defined in the Summaryof the Invention) can be prepared according to Scheme 3.

An intermediate of formula 14 is prepared by reacting an intermediate offormula 13 with a primary amine R¹NH₂ in a solvent such as water andwith heating. 14 is then treated with iodine monochloride in a solventsuch as methanol at around 0° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form15. After completion the residue is triturated with acetone. Theintermediate 15 is then reacted in a solvent, such as DMA, with ethylacrylate in the presence of a base, such as triethylamine, and in thepresence of a catalyst, such as Pd(OAc)₂, and (+)BINAP. The reaction isheated to approximately 100° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form16. 16 is then optionally purified by column chromatography. 26 can thenbe prepared from 16 by using the same reaction conditions as describedin Scheme 1 (starting at the point of the preparation of 5 from 4).

The intermediate 26 is then reacted with R^(2b)I in the presence of apalladium (II) catalyst such asacetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium (II) orchloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium(II) and a base such as sodium t-butoxide to provide compounds withgeneral structure 8.

A compound of the invention where R¹ is optionally substituted alkyl, R⁴is methyl or ethyl, R⁶ is phenyl or heteroaryl each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups (as defined inthe Summary of the Invention), and R² is R^(2a) or R^(2b) each asdefined in the Summary of the Invention can alternatively be preparedaccording to Scheme 4.

The intermediate of formula 12, prepared as described above, AKnovenegal-type condensation with 12 and an arylacetonitrile in thepresence of a base such as potassium carbonate or sodium hydroxide in aprotic solvent provides the cyclized imine 24. Acetylation of the iminewith acetic anhydride is required prior to hydrolysis which takes placein the presence of aqueous acid and heating to afford 25. Subsequently,25 can be oxidized to the corresponding sulfone with m-CPBA at roomtemperature and displaced with an amine of formula R²NH₂ where toprovide 26. 26 can then be used to prepare a Compound of the Inventionusing procedures in Scheme 3.

A compound of the invention where R¹ is optionally substituted alkyl, R⁴is methyl or ethyl, R⁶ is acetyl, and R^(2a) is as defined in theSummary of the Invention can alternatively be prepared according toScheme 4.

The addition of an oxidant such as m-CPBA to 6 provides the methylsulfone which can be subsequently displaced by various alkylamines andarylamines (R^(2a)NH₂) to afford 27. The addition of an acetate group atthe 6-position can be carried in the presence oftributyl-1-ethylvinyltin and a palladium catalyst such as Pd(PPh₃)₄ toprovide compounds with general structure I(b).

SYNTHETIC EXAMPLES Intermediate 12-amino-8-ethyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g,0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g,0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature.The reaction mixture was stirred overnight. After neutralizing to pH=8,the solid was collected through filtration followed by drying undervacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one(57.2 g, 95% yield) of product. ¹H NMR (400 MHz, DMSO-d6): δ 12.47 (bs,1H), 5.96 (bs, 1H), 2.47 (s, 3H), 2.17 (s, 3H).

To the round bottom flask containing6-methyl-2-(methylthio)pyrimidin-4(3H)-one (19 g, 121.6 mmol) was addedPOCl₃ (30 mL). The reaction mixture was heated to reflux for 2 h andthen concentrated on a rotary evaporator to dryness. The crude4-chloro-6-methyl-2-(methylthio)pyrimidine was used directly in the nextreaction without further purification.

To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added30 mL of a solution of 70% ethylamine in water. The reaction mixture washeated to 50° C. for 3 h. After completion, excess ethylamine wasevaporated on rotary evaporator under vacuum. The solid was filtered anddried under vacuum to affordN-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 90% yield).

To the solution of N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7mmol) in small portions at 0° C. Then the reaction mixture was stirredovernight. After evaporation of solvent, the residue was triturated withacetone. The productN-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimin-4-amine (25.2 g, 75%yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 5.37 (bs,1H), 3.52 (q, J=7.2 Hz, 1H), 2.50 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

To the solution of N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimin-4-amine(25.2 g, 81.48 mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g,122.2 mmol), Pd(OAc)₂ (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine(24.68 g, 244.4 mmol). Then the reaction mixture was heated to 100° C.and reacted overnight. After evaporation of solvent, the residue wasdiluted with water and the aqueous layer was extracted with ethylacetate. The product(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(16.8 g, 73% yield) was isolated by silica gel column chromatographywith 6-8% ethyl acetate in hexane as eluent. ¹H NMR (400 MHz, CDCl₃): δ7.65 (d, J=16.4 Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 5.15 (bs, 1H), 4.28(q, J=7.2 Hz, 2H), 3.54 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H),1.35 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).

To a solution of(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(16.8 g, 59.8 mmol) in DIPEA was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at roomtemperature. Then the reaction mixture was heated to reflux and reactedfor 15 h. After evaporation of solvent, the residue was triturated withacetone. The product8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77g, 77% yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ7.78 (d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H),2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

To a solution of8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.31 g,26.84 mmol) in DCM was added Br₂ (4.79 g, 29.52 mmol) dropwise at roomtemperature. Then the reaction mixture was stirred at room temperatureovernight. After filtration the solid was suspended in DCM (100 mL), andtriethylamine (20 mL) was added. The mixture was washed with water anddried with Na₂SO₄, and the product6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(6.96 g, 83% yield) was obtained after evaporation of DCM. ¹H NMR (400MHz, CDCl₃): δ 8.22 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.62(s, 3H), 1.34 (t, J=7.2 Hz, 3H).

To a solution of6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.765 g, 2.43 mmol) in DME-H₂O (10:1 11 mL) was added1H-pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withCH₂Cl₂ (Pd(dpppf), 0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29mmol) at room temperature. Then the reaction mixture was heated toreflux and reacted for 4 h. After cooling down to room temperature, thereaction mixture was partitioned with water and ethyl acetate. Afterseparation, the organic layer was dried with Na₂SO₄, and the product8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.567 g, 77% yield) was obtained by silica gel column chromatography.¹H NMR (400 MHz, CDCl₃): δ 13.3 (bs, 1H), 8.54 (s, 1H), 7.82-7.07 (m,2H), 4.45 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.2Hz, 3H).

To the solution of8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.123 g, 0.41 mmol) in DCM (2 mL) was added MCPBA (0.176 g, 77%, 0.785mmol) in a small portion at room temperature. Then the reaction mixturewas stirred for 4 h. After evaporation of DCM, dioxane (1 mL) and liquidammonia (1 mL) were introduced. The reaction was stirred at roomtemperature overnight. The product2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(50.4 mg) was obtained by silica gel column chromatography. ¹H NMR (400MHz, CD₃OD): δ 8.41 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 6.96 (d, J=2.0 Hz,1H), 4.51 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 1.29 (t, J=7.2 Hz, 3H); MS(EI) for C₁₃H₁₄N₆O: 271.3 (MH⁺).

Intermediate 2 Alternate route to(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate

N,N-Dimethyl acetamide dimethyl acetal (75 g, 0.56 mole) was added to asuspension of thiourea (33.0 g, 0.43 mole) in methylene chloride. Themixture was heated under reflux for 4 h. The solvent was removed and theresidue was crystallized from 5% MeOH and diethyl ether affording(1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 76%yield).

A suspension of (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide(47.8 g, 0.33 mole) in methyl iodide (150 mL) and THF (350 mL) wasstirred for 18 h at room temperature. The mixture was evaporated underreduced pressure. After addition of 5% MeOH and diethyl ether, thecompound precipitated and was collected by filtration affording(1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogeniodide salt (91.0 g, 96% yield).

To a solution of(1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogeniodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), wasadded ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole)was added under a nitrogen atmosphere. The mixture was stirred for 4 hat room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78mole) was added. The reaction mixture was stirred overnight. The solventwas removed and H₂O was added. The pH was adjusted to pH=5.0 with aceticacid and extracted with ethylacetate then evaporated and crystallizedfrom the appropriate solvent (Ethylacetate-Hexanes mixture solvent,approximately 20% ethylacetate-Hexanes). This afforded ethyl4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5g, 62% yield) after drying under vacuum.

A solution of ethyl4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 g,0.26 mole) and phosphorous oxychloride (POCl₃, 320 mL) was heated underreflux for 4 to 5 h (monitor reaction by TLC using 30% ethylacetate andhexanes). After completion of reaction, phosphorous oxychloride wasremoved on a rotary evaporator. The residue was poured on to ice waterand extracted with ethylacetate several times. The combined organiclayers were evaporated, on a rotary evaporator, to give crude ethyl4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g). Thiscompound was used without purification.

To a solution of ethyl4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g) in THF(1000 mL) and triethylamine (110 mL, 0.81 mole) was added ethylamine(2.0 M in THF, 0.81 mole) at 0° C. This reaction mixture was stirred atroom temperature overnight and then solvents were removed on a rotaryevaporator. H₂O was added and the mixture extracted with ethyl acetateseveral times. Solvents from the combined organic layers were removed ona rotary evaporator affording 58 g (86% yield) of ethyl4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate. Thismaterial was used as such without further purification.

To a lithium aluminum hydride solution (LAH, 1.0 M solution in THF,Aldrich, 450 mL) was added a solution of ethyl4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (57 g) inTHF (1000 mL). The reaction mixture was stirred overnight. After coolingto 0° C., the reaction mixture was cautiously quenched with a 1:9mixture of H₂O/THF until gas evolution has ceased, then diluted with H₂O(500 mL) and stirred well for 2 h. The resulting slurry was extractedwith ethylacetate several times. The aqueous layer was then filteredthrough Celite and washed with ethylacetate again. The combined organiclayers were washed with brine, dried and concentrated under reducedpressure to give 41.0 g (85% yield) of[4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol as alight yellow crystal, which was used without purification in the nextstep.

To a solution of[4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol (41.0 g)in chloroform (4000 mL) was added manganese oxide (125 g, 1.4 mole) andstirred for 4 h at room temperature. More manganese oxide was addeduntil the disappearance of alcohol compound was observed. The reactionmixture was filtered through Celite and washed with some chloroform andevaporated all organic solvents to give 38 g (92% yield) of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde as acolorless solid, which was used without purification in the next step.

To a solution of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (38 g,180 mmol) in THF (500 mL) was added (Carbethoxymethylene)triphenylphosphorane (95%, Aldrich, 85.18 g, 244 mmol). The reactionmixture was heated to reflux for 1.5 h and was monitered by TLC (4:1hexanes/ethylacetate). The reaction was cooled to room temperature andwas concentrated on a rotary evaporator. It was directly subjected tocolumn chromatography (4:1 hexanes/ethylacetate) to give(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylateas a white crystal, 46.14 g (91% yield).

(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylatewas converted to8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one asdescribed above in Intermediate 1.

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one and8-cyclopentyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one.

Intermediate 32-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a 3-necked 3-L flask, that was equipped with an overhead stirrer, wasadded in order 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 100 g,0.696 mol, 1 equiv.), ethylamine (70% ethylamine in water, Lancaster,625 mL), 625 mL H₂O, and 125 mL TEA (0.889 mol, 1.28 equiv.). Themixture was stirred and heated at reflux for 20 h, during which time thereaction turned homogeneous. The reaction was allowed to cool to roomtemperature. The volatile ethylamine was removed on a rotary evaporator.A precipitate formed. The aqueous mixture containing the precipitate wasallowed to stand at room temperature for 2 h and then filtered. Afterdrying under vacuum, 106 g (100% yield) of2-amino-6-ethylaminopyrimidine was obtained as a colorless solid. Thismaterial was used as such in the following reaction.

To a solution of 2-amino-6-ethylaminopyrimidine (98 g, 0.64 mol) inmethanol (1.6 L) was added IC1 (115.0 g, 0.71 mol) in a small portion at15° C. Then the reaction mixture was stirred at room temperature for 3 h(monitored by LC/MS). After evaporation of solvent by rotary evaporator,the residue was triturated with acetone.2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 93%isolated yield) was obtained by vacuum filtration and drying. ¹H NMR(400 MHz, CD₃OD) δ 3.58 (q, 2H), 2.14 (s, 3H), 1.11 (t, 3H); MS (EI) forC₇H₁₁N₄ClI: 279.1 (MH⁺).

To a three-neck round bottom flask equipped with over-head mechanicstirrer were added 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride(188.5 g, 0.60 mol), ethyl acrylate (221 mL, 2.0 mol), triethylamine(285 mL, 2.0 mol), DMF (1.3 L), andtetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄, 31.3 g, 0.027 mol).The reaction mixture was heated to 95° C. and stirred for 3 h (monitoredby LC/MS). After reaction completion, the reaction mixture wasevaporated about to 1/10 of original volume and partitioned with 500 mLof ethyl acetate and 1000 mL of water. The aqueous layer was extractedwith ethyl acetate 5 times. (E)-Ethyl3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (100 g, 67%yield) was obtained by recrystallization from acetone after evaporationof ethyl acetate. ¹H NMR (400 MHz, CD₃OD) δ 7.48 (dd, J1=16.0 Hz, J2=4.0Hz, 1H), 6.20 (dd, J1=16 Hz, J2=4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.51(q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.3 (t, J=7.2 Hz, 3H), 1.2 (t, J=7.6Hz, 3H). MS (EI) for C₁₂H₁₈N₄O₂: 251.3 (MH⁺).

(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate(4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and themixture was heated to 165° C. and stirred for 24 h. After that, themixture was cooled to 70° C. followed by the addition of H₂O (20 mL) toprecipitate crystal and stirred for 1 h at room temperature. The crystalwas collected and washed with H₂O and acetone and dried under vacuum toafford 2.70 g (73.5% yield of2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a lightyellowish brown solid. LC/MS: Calculated for C₁₀H₁₂N₄O (204.2). Found:205.31 (MH⁺); HPLC analytical purity: 98.5%.

2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL,1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 hat room temperature. After that, the solvent was evaporated nearly 80%volume of reaction mixture under vacuum, and then acetone was added togive 3.54 g2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as atan solid. LC/MS: Calculated for C₁₀H₁₁BrN₄O (283.12). Found: 285.15(M+2). HPLC analytical purity: 97.7%.

Intermediate 48-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

POCl₃ (250 mL) was added to a 500 mL round bottom flask charged with15.0 g of 6-methyl-2-(methylthio)pyrimidin-4(3H)-one. The reactionmixture was topped with a Vigreux column and allowed to stir undernitrogen at 90° C. After 4 h, LCMS indicated desired product had formedin high yield. POCl₃ was removed by rotary evaporation and azeotropedwith 2×300 mL CHCl₃ and 2×300 mL toluene.4-Chloro-6-methyl-2-(methylthio)pyrimidine as a thick yellow oil wasplaced under heavy vacuum for several hours, and then used immediatelyin the next reaction.

Isopropylamine (100 mL) was added very slowly to 22.0 g (125.96 mmol) ofcrude 4-chloro-6-methyl-2-(methylthio)pyrimidine in 70 mL of THF in a350 mL pressure tube. NOTE: Residual POCl₃ caused smoking and bubbling,therefore the addition was done at 0° C. Once acid was quenched, anadditional 50 mL of isopropylamine was added and the pressure tube wassealed. The reaction vessel was brought to 60° C. and stirred overnight.The LCMS indicate very little starting material. Solvent was evaporatedleaving N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine as aviscous yellow oil. The crude material was taken directly to the nextstep.

To a crude solution ofN-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol),prepared using analogous procedures as described in Example 1, in 400 mLof methanol was added IC1 (40.0 g, 246 mmol) in small portions at roomtemperature. The reaction mixture was then stirred at for 3 h monitoringby LC/MS. After evaporation of solvent by rotary evaporator, the residuewas triturated with acetone to yield5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. ¹H NMR (400MHz, CDCl₃) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H),1.41 (d, J=6.4, 6H).

5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolylphosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMAin a pressure tube and sealed. The reaction mixture was heated to 100°C. and allowed to stir overnight. The reaction was quenched byfiltration through a short silica plug washing with ACN. The solvent wasevaporated and diluted with ethyl acetate then extracted with 10%aqueous LiCl, followed by water and brine. NOTE: Extraction is necessaryto remove all DMA giving resolution in chromatography. The sample waspurified by silica gel column chromatography using 20% ethylacetate/hexane as eluent. Desired fractions were combined and reduced toafford 2.5 g (34% yield) of ethyl(2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylateas a yellow/orange oil.

(E)-Ethyl3-(4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(2.5 g, 8.46 mmol) was dissolved in acetic acid by gentle warming.Sample was placed in microwave reactor for 6 h at 180° C., 300 W, and200 PSI. The product was purified by silica gel column chromatographyeluting with 20% ethyl acetate/hexane. Desired fractions were combinedand reduced into8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as ayellow powder (1.20 g, 57% yield) which was then dried under heavyvacuum overnight. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=9.6, 1H), 6.58(d, J=9.6, 1H), 5.84 (br s, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 1.63 (d,J=6.8, 6H).

8-Isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(5.38 g, 21.59 mmol) was dissolved in 100 mL DCM. To the stirringsolution, m-CPBA (13.97 g, 64.78 mmol) was added. The reaction wasallowed to stir for 2.5 h at room temperature. LCMS indicated reactionhad gone to completion. Sample was diluted with 300 mL of DCM and 300 mLK₂CO₃, upon addition of base a white precipitate formed that dissolvedin excess H₂O. Organic layer was extracted further with H₂O and brine,and then dried over Na₂CO₃. The solvent was evaporated to afford8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(6.0 g, 99% yield) as a light yellow oil that was used immediately inthe next reaction.

Using the same or analogous synthetic techniques and substituting withappropriate reagents,8-cyclopentyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-onewas prepared.

Intermediate 52-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(approximately 3.0 g) was dissolved in 50 mL THF, in a 350 mL pressuretube. While stirring, NH₃ (g) was bubbled in through solution for 1.5minutes. A color change was observed form light yellow to olive green inabout 120 seconds. The tube was sealed and stirred at room temperatureovernight. A precipitate had formed. The reaction mixture, includingprecipitate, was reduced to near dryness, filtered and washed with aminimal volume of cold THF, affording 2.88 g of2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

To a solution of2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.88 g,13.19 mmol) dissolved in 80 mL of DCM at 0° C., (4.21 g, 26.39 mmol)bromine was added. Reaction vessel was removed from ice bath and allowedto react at room temperature over night. LCMS indicated completeconversion of starting material to product. Sample was evaporated toremove DCM and excess bromine. Orange solid was diluted in ethyl acetateand extracted with 10% NaHSO₃, H₂O, and brine. Organic layer was driedover Na₂SO₄, filtered, and reduced to dryness yielding2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one asa light yellow powder (2.2 g, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.08(s, 1H), 5.83 (m, 1H), 5.69 (br s, 2H), 2.60 (s, 3H), 1.58 (d, J=6.8,6H).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:6-bromo-8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-oneand6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one.

Intermediate 6

In a 350 mL pressure tube2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(1.50 g, 5.05 mmol), 1H-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol),K₂CO₃ (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium(0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H₂O.The tube was sealed, heated to 100° C. and allowed to react overnight. Acolor change was observed. LCMS indicated no presence of startingmaterial. Sample was filtered through a syringe filter and evaporated todryness. Compound was dissolved in ethyl acetate and triturated inhexane. Light yellow powder of2-amino-8-isopropyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(195 mg, 13.7% yield) was found to be 98% pure by HPLC. ¹H NMR (400 MHz,CDCl₃) δ 12.97 (br s, 1H), 8.35 (s, 1H), 7.60 (br s, 1H), 7.21 (s, 2H),6.94 (s, 1H), 5.86 (br s, 1H), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) forC₁₄H₁₆N₆O: 285.0 (MH⁺).

Example 16-bromo-2-{[4-(2-diethylamino)ethyl]piperazin-1-yl}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

3-Chloroperbenzoic acid (0.565 g, 3.27 mmol) was added to a solution of6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.308 g, 0.980 mmol) in dichloromethane (5.0 mL) at room temperature.After 30 minutes, the reaction was diluted with dichloromethane (50 mL)and washed twice with saturated NaHCO₃, followed by brine. The organicphase was separated and dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was precipitated with ethyl acetate to provide8-ethyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (302mg, 89% yield) as a yellow solid.

To a 15 mL pressure tube was added8-ethyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(70.0 mg, 0.202 mmol), 1 mL dimethylsulfoxide (dmso), and4-morpholinoaniline (Aldrich, 72.9 mg, 0.409 mmol, 2 eq,) was added. Thereaction mixture was heated to 100° C. for 16 h. The reaction wasdiluted with EtOAc, washed with sat. aqueous NaHCO₃, dried over Na₂SO₄,filtered, and concentrated. The crude material was purified bypreparative hplc using 20-90% ACN in H₂O with 0.05% THF. The desiredproduct containing fractions were combined, diluted with EtOAc, andwashed with saturated NaHCO₃, H₂O, and brine. The organic layer wasdried over Na₂SO₄ and solvent was removed on a rotary evaporator to acolorless film. The film was dissolved in 2 mL ACN and 2 mL H₂O, frozenand lyophilized overnight, yielding 8.7 mg (10% yield) of6-Bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-oneas a colorless powder: ¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 7.56 (d,J=8.8 Hz, 2H), 7.22 (s, 1H), 6.94 (d, J=9.2 Hz, 2H), 4.50 (q, J=7.2 Hz,2H), 3.88 (t, J=4.4 Hz, 4H), 3.15 (t, J=5.2 Hz, 4H), 1.58 (s, 3H), 1.35(t, J=6.8 Hz, 3H), MS (EI) for C₂₀H₂₂BrN₅O₂: 444.3 (MH⁺)

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 2

6-Bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 5.89 (bs, 1H), 4.49 (bd, 2H),2.51 (s, 3H), 2.07 (m, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.31 (t, 3H), MS(EI) for C₁₅H₁₉BrN₄O: 351.2 (MH⁺)

Example 3

6-Bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 5.41 (bs, 1H), 4.47 (bd, 2H),3.84 (bs, 1H), 2.51 (s, 3H), 2.05 (d, J=12.4 Hz, 2H), 1.77 (m, 2H), 1.64(br m, 4H), 1.39 (m, 2H), 1.30 (m, 3H), MS (EI) for C₁₆H₂₁BrN₄O: 365.2(MH⁺)

Example 4

6-Bromo-8-ethyl-4-methyl-2-(2-morpholinoethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 6.22 (bs, 1H), 4.48 (q, J=6.4Hz, 2H), 3.74 (t, J=4.4 Hz, 1H), 3.57 (q, J=4.8 Hz, 3H), 2.98 (bs, 2H),2.63 (t, J=6.0 Hz, 2H), 2.53 (s, 3H), 1.30 (t, J=6.8 Hz, 2H), MS (EI)for C₁₆H₂₂BrN₅O: 396.2 (MH⁺)

Example 5

6-Bromo-8-ethyl-4-methyl-2-[(3-morpholino-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 6.23 (bs, 1H), 4.47 (bs, 1H),3.75 (m, 4H), 3.57 (m, 2H), 2.52 (m, 4H), 2.48 (m, 2H), 1.82 (m, 2H),1.28 (s, 3H), MS (EI) for C₁₇H₂₄BrN₅O: 410.2 (MH⁺)

Example 6

6-Bromo-8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (bs, 1H), 8.46 (s, 1H), 7.64 (d, J=9.2Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 4.36 (d, J=6.8 Hz, 2H), 3.08 (t, J=4.4Hz, 4H), 2.58 (s, 3H), 2.44 (t, J=4.8 Hz, 4H), 2.21 (s, 3H), 1.24 (t,J=7.2 Hz, 3H), MS (EI) for C₂₁H₂₅BrN₆O: 457.0 (MH⁺)

Example 7

6-Bromo-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 9.80 (bs, 1H), 8.12 (s, 1H), 7.54 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.68 (m, 4H),2.54 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.23 (t, J=5.6 Hz, 3H), MS (EI)for C_(22H27)BrN₆O: 471.4 (MH⁺)

Example 8

2-{[4-(4-Benzylpiperazin-1-yl)phenyl]amino}-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 7.53 (d, J=7.0 Hz, 2H), 7.35(m, 4H), 7.29 (m, 1H), 7.20 (m, 1H), 6.94 (d, J=6.8 Hz, 2H), 4.48 (q,J=6.0 Hz, 2H), 3.59 (s, 2H), 3.20 (s, 4H), 2.64 (s, 4H), 2.59 (s, 3H),1.34 (t, J=7.6 Hz, 3H), MS (EI) for C₂₇H₂₉BrN₆O: 534.5 (MH⁺)

Example 12

6-Bromo-8-ethyl-2-[(2-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.47 (td, J=8.0, 4.0 Hz, 1H), 8.18 (s, 1H),7.53 (bs, 1H), 7.17 (m, 2H), 7.06 (m, 1H), 4.53 (q, J=6.8 Hz, 2H), 2.64(s, 3H), 2.43 (m, 4H), 1.37 (t, J=7.2 Hz, 3H); MS (EI) for C₁₆H₁₄BrFN₄O:376.9 (M⁺).

Example 14

6-Bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.32 (m, 5H), 5.86 (bs, 1H),4.68 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.13 (t, J=7.2 Hz,3H); MS (EI) for C₁₇H₁₇BrN₄O: 375.1 (MH⁺).

Example 15

6-Bromo-8-ethyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 1H), 7.68-7.10 (m, 5H), 4.53 (q,J=6.80 Hz, 2H), 2.62 (s, 3H), 1.36 (t, J=6.80 Hz, 3H); MS (EI) forC₁₆H₁₅BrN₄O: 361.1 (MH⁺).

Example 16

8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 13.05 (bs, 1H), 10.05 (bs, 1H), 8.47 (s,1H), 7.76 (m, 2H), 7.65 (bs, 1H), 7.21 (m, 2H), 6.99 (s, 1H), 5.97 (m,1H), 2.69 (s, 3H), 2.30 (m, 2H), 1.95 (m, 2H), 1.79 (m, 2H), 1.63 (m,2H); MS (EI) for C_(22H21)FN₆O: 405.1 (MH⁺).

Example 17

8-Cyclopentyl-4-methyl-2-(phenylamino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 7.64 (m, 2H), 7.40 (t, J=8.0Hz, 1H), 7.35 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.71 (bs, 1H), 6.05(pent, J=8.0 Hz, 1H), 2.73 (s, 3H), 2.41 (m, 2H), 2.05 (m, 2H), 1.89 (m,2H), 1.71 (m, 2H); MS (EI) for C_(22H22)N₆O: 387.1 (MH⁺).

Example 18

methyl2-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate;MS calculated for C₂₁H₂₂N₄O₃: 378.4298, MS (EI) observed 379.1 (MH⁺).

Example 19

methyl3-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate;MS calculated for C₂₁H₂₂N₄O₃: 378.4298, MS (EI) observed 379.2 (MH⁺).

Example 20

methyl4-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate;MS calculated for C₂₁H₂₂N₄O₃: 378.4298, MS (EI) observed 379.1 (MH⁺).

Example 21

8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₂₅H₃₂N₆O: 432.5688, MS (EI) observed 433.3 (MH⁺).

Example 22

8-isopropyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₂₃H₃₀N₆O: 406.531, MS (EI) observed 407.1 (MH⁺).

Example 23

8-cyclopentyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₁₉H₂₀N₄O₃: 320.394, MS (EI) observed 321.2 (MH⁺).

Example 24

6-bromo-8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;¹H NMR (400 MHz, DMSO-d₆): δ 9.90 (br, 1H), 9.30 (br, 1H), 8.50 (s, 1H),7.50 (m, 2H), 6.80 (m, 2H), 5.80 (m, 1H), 2.60 (s, 3H), 2.20 (m, 2H),1.98 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H); MS (EI) for C₁₉H₁₉BrN₄O₂:416.8 (M+H); MS calculated for C₁₉H₁₉BrN₄O₂: 415.2891, MS (EI) observed416.5 (MH⁺).

Example 25

8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₁₉H₂₀N₄O₂: 336.393, MS (EI) observed 337.2 (MH⁺).

Example 26

8-cyclopentyl-4-methyl-2-{[4-(methyloxy)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₂₀H₂₂N₄O₂: 350.4198, MS (EI) observed 351.2 (MH⁺).

Example 27

8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₂₃H₂₈N₆O.HCl: 404.5152, MS (EI) observed 405.0 (MH⁺).

Example 28

8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₁₉H₁₉FN₄O: 338.3841, MS (EI) observed 339.0 (MH⁺).

Example 29

8-cyclopentyl-4-methyl-2-[(4-aminophenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C₁₉H₂₁N₅O: 335.4089, MS (EI) observed 336.2 (MH⁺).

Example 30

8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;MS calculated for C_(22H22)N₆O: 386.4568, MS (EI) observed 387.1 (MH⁺).

Example 312-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one

3-Chloroperbenzoic acid (1.78 g, 10.4 mmol) was added to a solution of6-bromo-4-methyl-8-(1-methylethyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(1.33 g, 4.14 mmol), prepared using procedures similar to thosedescribed in Example 1, in dichloromethane (30.0 mL) at roomtemperature. After 1, the reaction was diluted with dichloromethane (50mL) and washed twice with saturated NaHCO₃, followed by brine. Theorganic phase was separated and dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was precipitated with ethylacetate/hexanes to provide the corresponding sulfone (1.31 g, 93% yield)as an off-white solid.

Anhydrous DMSO (4.0 mL) was added to a pressure tube charged with theabove sulfone (253 mg, 0.702 mmol) and4-(4-ethylpiperazin-1-yl)phenylamine (159 mg, 0.773 mmol). The pressuretube was sealed and heated to 100° C. After 12 hours, the reaction wascooled to room temperature and poured into water (100 mL) and dilutedwith ethyl acetate (100 mL). The aqueous phase was separated and washedwith an additional amount of ethyl acetate (100 mL). The organic layerswere pooled, washed with brine, and dried over Na₂SO₄, filtered andconcentrated in vacuo to afford6-bromo-2-(4-(4-ethylpiperazin-1-yl)phenylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one.The compound was used in the next step without further purification.

Pd(dppf) dichloromethane adduct (115 mg, 0.141 mmol) was added to asuspension of6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(341 mg, 0.703 mmol), 2-thiophene boronic acid (99 mg, 0.77 mmol), andtriethylamine (245 μL, 1.76 mmol) in 10:1 DME: water (6.6 mL). Thereaction was heated to 100° C. After 24 h, the reaction was cooled toroom temperature, diluted with water (50 mL) and filtered though aCelite plug and concentrated in vacuo. The residue was purified onreverse phase HPLC (25 mM ammonium acetate:acetonitrile, 30-80%gradient). The fractions containing product were collected andlyophilized to give2-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one.(23 mg, 7% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl₃): δ 8.08 (s,1H), 7.63 (bd, J=3.2 Hz, 1H), 7.51 (m, 2H), 7.40 (bd, J=4.4 Hz, 1H),7.11 (m, 2H), 6.97 (m, 2H), 5.90 (sept, 1H), 3.23 (m, 4H), 2.68 (s, 3H),2.65 (m, 4H), 2.50 (q, J=7.2 Hz, 2H), 1.63 (d, J=6.8 Hz, 6H), 1.15 (t,J=7.2 Hz, 3H); MS (EI) for C₂₇H₃₂N₆OS: 489.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 32

6-Bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.47 (m, 2H), 7.17 (bs, 1H),6.96 (m, 2H), 5.84 (sept, 1H), 3.24 (m, 4H), 2.66 (m, 4H), 2.58 (s, 3H),2.51 (q, J=7.6 Hz, 2H), 1.57 (d, J=6.8 Hz, 6H), 1.15 (t, J=7.2 Hz, 3H);MS (EI) for C₂₃H₂₉BrN₆O: 486.0 (MH⁺).

Example 33

2-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.78 (bs, 1H), 7.98 (s, 1H), 7.67 (m, 2H),7.59 (m, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 6.93 (m, 2H), 5.83 (bs, 1H),3.09 (m, 4H), 2.64 (s, 3H), 2.65 (m, 4H), 2.49 (m, 4H), 2.36 (q, J=7.2Hz, 2H), 1.56 (d, J=6.8 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H); MS (EI) forC₂₉H₃₄N₆O: 483.1 (MH⁺).

Example 34

6-(3,5-Difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 11.29 (bs, 1H), 10.14 (bs, 1H), 8.23 (s,1H), 7.74 (m, 2H), 7.57 (m, 2H), 7.23 (m, 1H), 7.04 (m, 2H), 4.39 (m,3H), 3.77 (bd, J=12.4 Hz, 2H), 3.54 (bd, J=11.2 Hz, 2H), 3.20-3.12 (m,5H), 2.69 (s, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H); MS(EI) for C_(28H30)F₂N₆O: 505.1 (MH⁺).

Example 35

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 1H), 7.58 (m, 2H), 7.47-7.36 (m,3H), 7.20 (bs, 1H), 7.06 (m, 1H), 6.97 (m, 2H), 4.52 (q, J=8.0 Hz, 2H),3.25 (m, 4H), 2.65 (m, 4H), 2.64 (s, 3H), 2.50 (q, J=4.0 Hz, 2H), 1.38(t, J=8.0 Hz, 3H), 1.15 (t, J=8.0 Hz, 3H); MS (EI) for C_(28H31)FN₆O:487.1 (MH⁺).

Example 36

2-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.50(m, 2H), 7.19 (bs, 1H), 6.98 (m, 2H), 6.68 (bs, 1H), 5.90 (bsept, J=6.4Hz, 1H), 3.24 (m, 4H), 2.68 (s, 3H), 2.65 (m, 4H), 2.50 (q, J=6.8 Hz,2H), 1.62 (d, J=6.8 Hz, 3H), 1.15 (t, J=7.6 Hz, 3H); MS (EI) forC₂₆H₃₂N₈O: 473.4 (MH⁺).

Example 37

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.95 (bs, 1H), 7.82 (m, 1H), 7.68 (d, J=8.8Hz, 2H), 7.61 (m, 2H), 7.45 (m, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.94 (d,J=9.2 Hz, 2H), 4.40 (q, J=6.8 Hz, 2H), 3.10 (t, J=4.4 Hz, 2H), 2.66 (s,3H), 1.28 (t, J=6.8 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H), MS (EI) forC_(28H31)FN₆O: 487.1 (MH⁺)

Example 38

8-Ethyl-4-methyl-2-{[4-(2-morpholin-4-ylethoxy]phenyl}amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.95 (bs, 1H), 8.05 (s, 1H), 7.72 (m, 3H),7.43 (m, 3H), 7.36 (m, 1H), 6.94 (d, J=8.8 Hz, 2H), 4.40 (q, J=7.2 Hz,2H), 4.07 (t, J=6.0 Hz, 2H), 3.58 (t, J=16.0 Hz, 4H), 2.67 (m, 4H), 2.66(s, 3H), 1.28 (t, J=6.8 Hz, 3H), MS (EI) for C_(28H31)N₅O₃: 486.4 (MH⁺)

Example 39

8-Cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 12.92 (bs, 1H), 9.80 (bs, 1H), 8.41 (s,1H), 7.54 (d, J=8.4 Hz, 2H), 6.97 (m, 1H), 6.93 (d, J=8.8 Hz, 2H), 5.97(s, 1H), 3.10 (s 3H), 2.65 (s, 2H), 2.38 (m, 2H), 2.30 (m, 2H), 1.91(bs, 2H), 1.77 (bs, 2H), 1.61 (bs, 2H), 1.04 (t, J=6.8 Hz, 3H), MS (EI)for C_(28H34)N₈O: 499.1 (MH⁺)

Example 40

8-Ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 1H), 7.68 (d, 1H), 7.60 (dd, 2H),7.41 (dd, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 6.98 (dd, 2H), 4.58 (qr, 2H),3.31 (bs, 4H), 2.80 (bs, 4H), 2.68 (s, 3H), 2.55 (bs, 3H), 1.42 (t, 3H);MS (EI) for C₂₅H₂₈N₆OS: 461.1 (MH⁺).

Example 41

8-Ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 7.65 (d, 1H), 7.58 (m, 2H),7.37 (m, 4H), 7.29 (m, 1H), 7.19 (s, 1H), 7.18 (qr, 1H), 6.98 (m, 2H),4.58 (m, 2H), 3.60 (d, 2H), 3.20 (m, 4H), 2.68 (s, 3H), 2.62 (m, 4H),1.56 (s, 3H), 1.40 (t, 3H); MS (EI) for C₃₁H₃₂N₆OS: 537.1 (MH⁺).

Example 42

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 7.69 (d, 1H), 7.59 (m, 2H),7.41 (dd, 1H), 7.20 (s, 1H), 7.15 (m, 1H), 6.97 (m, 2H), 4.58 (m, 2H),3.22 (m, 4H), 2.71 (s, 4H), 2.65 (m, 3H), 2.50 (m, 2H), 1.40 (t, 3H),1.18 (t, 3H); MS (EI) for C₂₆H₃₀N₆OS: 475.1 (MH⁺).

Example 43

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 7.85 (s, 1H), 7.60 (dd, 2H),7.51 (d, 1H), 7.18 (s, 1H), 6.98 (d, 2H), 6.82 (s, 1H), 4.55 (qr, 2H),3.22 (m, 4H), 2.65 (s, 3H), 2.62 (m, 4H), 2.58 (m, 2H), 1.39 (t, 3H),1.18 (t, 3H); MS (E1) for C₂₆H₃₀N₆O₂: 459.1 (MH⁺).

Example 44

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, 1H), 7.60 (m, 3H), 7.00 (d, 2H),6.65 (s, 1H), 4.58 (m, 2H), 3.25 (m, 4H), 2.72 (s, 3H), 2.65 (m, 4H),2.50 (m, 2H), 1.40 (t, 3H), 1.18 (t, 3H); MS (EI) for C₂₅H₃₀N₈O: 459.4(MH⁺).

Example 45

8-Cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.69 (s, 1H), 8.20 (s, 1H), 7.58 (dd, 2H),7.40 (s, 1H), 7.15 (d, 2H), 6.00 (bs, 1H), 3.65 (m, 1H), 3.78-3.60 (m,1H), 3.43 (m, 8H), 2.81 (s, 3H), 2.34 (m, 2H), 1.82 (m, 4H), 1.62 (m,2H); MS (EI) for C₂₆H₃₀N₈OS: 471.1 (MH⁺).

Example 46

8-Ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

8-Ethyl-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one(275 mg, 0.80 mmol) and 4-(4-ethylpiperazin-1-yl)aniline (197 mg, 1.2equiv.) were added to dimethyl sulfoxide (5 mL) and the resultingmixture was heated to 100° C. and stirred overnight. After cooling toroom temperature, the reaction was partitioned between aqueous andorganic layers with ethyl acetate and H₂O, organic layer was dried withanhydrous magnesium sulfate, filtered and evaporated, and directlyapplied to prep-LC to provide the title compound in (210.0 mg, 56%yield): ¹H NMR (400 MHz, CDCl₃): δ 7.80 (s, 1H), 7.62 (d, 2H), 7.60 (d,2H), 7.40 (m, 2H), 7.18 (s, 1H), 6.95 (d, 2H), 4.50 (q, 2H), 3.22 (m,4H), 2.70 (m, 4H), 2.60 (s, 3H), 2.50 (m, 2H), 1.40 (t, 3H), 1.20 (t,3H); MS (EI) for C_(28H32)N₆O: 469.10 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 47

2-[4-{[2-(Diethylamino)ethyl]oxy}phenyl]amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.00 (s, 1H), 7.62 (m, 4H), 7.40 (m, 3H),6.95 (m, 2H), 4.50 (q, 2H), 3.60 (m, 4H), 3.40 (m, 4H), 2.61 (s, 3H),1.40 (m, 9H); MS (EI) for C_(28H33)N₅O₂: 472.1 (MH⁺).

Example 48

8-Ethyl-2-[(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.82 (br, 1H), 9.20 (bs, 1H), 8.00 (s, 1H),7.80 (d, 2H), 7.60 (d, 2H), 7.40 (m, 3H), 6.85 (d, 2H), 4.40 (q, 2H),2.60 (s, 3H), 1.25 (t, 3H); MS (EI) for C_(22H20)N₄O₂: 373.1 (MH⁺).

Example 49

8-Ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 1H), 7.70-6.84 (m, 10H), 4.56 (q,J=7.20 Hz, 2H), 2.66 (s, 3H), 1.41 (t, J=7.20 Hz, 3H); MS (EI) forC_(22H20)N₄O: 357.1 (MH⁺).

Example 50

2-(cyclopropylamino)-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.40 (s, 1H), 7.62 (bs, 1H), 6.96 (bs,1H), 4.54 (bs, 2H), 2.85 (m, 1H), 2.66 (s, 3H), 1.33 (bs, 3H), 0.81 (m,2H), 0.59 (m, 2H); MS (EI) for C₁₆H₁₈N₆O: 311.3 (MH⁺).

Example 51

2-[(Cyclopropylmethyl)amino]-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.04 (s, 1H), 7.27 (bs, 1H), 6.60 (bs,1H), 4.20 (q, J=7.2 Hz, 2H), 3.05 (d, J=7.20 Hz, 2H), 2.34 (s, 3H), 1.04(t, J=7.2 Hz, 3H), 0.89 (m, 1H), 0.24 (m, 2H), 0.01 (m, 2H); MS (EI) forC₁₇H₂₀N₆O: 325.3 (MH⁺).

Example 52

8-Ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.34 (bs, 1H), 7.25 (bs, 1H), 6.90 (bs,1H), 4.60 (dt, J=5.2, 2.2 Hz, 2H), 4.49 (q, J=7.20 Hz, 2H), 3.78 (dt,J=5.2, 2.2 Hz, 2H), 2.64 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (EI) forC₁₅H₁₇FN₆O: 317.3 (MH⁺).

Example 53

8-Ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-Ethyl-2-(4-hydroxyphenylamino)-4-methyl-6-phenylpyrido[2,3-]pyrimidin-7(8H)-one(70 mg, 0.188 mmol) from above, 1-(2-chloroethyl)piperidinehydrochloride (245.0 mg, 1.331 mmol) and K₂CO₃ (450.0 mg, 3.261 mmol)were added to DMF (5 mL). The reaction was heated to reflux for tenminutes then cooled to room temperature and partitioned between aqueousand organic layers with ethyl acetate and H₂O. The organic layer wasdried with anhydrous magnesium sulfate, filtered and evaporated. Theresidue was directly applied to prep-LC to provide8-Ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one(17.0 mg, 77% yield): ¹H NMR (400 MHz, DMSO-d₆): δ 10.00 (bs, 1H), 8.10(s, 1H), 7.70 (m, 4H), 7.40 (m, 3H), 6.95 (d, 2H), 4.40 (q, 2H), 4.10(bs, 2H), 3.40 (bs, 6H), 2.60 (s, 3H), 1.60 (bs, 4H), 1.40 (bs, 2H),1.23 (t, 3H); MS (EI) for C₂₉H₃₃N₅O₂: 484.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 53

8-Ethyl-4-methyl-2-({4-[2-morpholin-4-ylethyl]oxyphenyl}amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d6): δ 10.00 (bs, 1H), 8.10 (s, 1H), 7.70 (m, 4H),7.40 (m, 3H), 6.95 (d, 2H), 4.40 (q, 2H), 4.10 (m, 2H), 3.60 (m, 4H),2.62 (q, 2H), 2.61 (s, 3H), 2.44 (m, 4H), 1.23 (t, 3H); MS (EI) forC_(28H31)N₅O₃: 486.1 (MH⁺).

Example 54

8-Cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenylamino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d6): δ 13.00 (br, 1H), 9.80 (br, 1H), 8.40 (s,1H), 7.60 (br, 1H), 7.50 (m, 2H), 6.98 (m, 3H), 6.00 (br, 1H), 3.40 (m,4H), 3.18 (m, 4H), 2.62 (s, 3H), 2.38 (m, 4H), 1.85 (m, 2H), 1.80 (m,2H), 1.60 (m, 2H), 1.00 (t, 3H); MS (EI) for C_(28H34)N₈O: 498.9 (M+H).

Example 55

6-Bromo-8-ethyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.20 (bs, 1H), 8.50 (s, 1H), 7.80 (m, 2H),7.20 (m, 2H), 4.40 (q, 2H), 2.60 (s, 3H), 1.28 (t, 3H); MS (EI) forC₁₆H₁₄BrFN₄O: 378.0 (M+H).

Example 57

6-Bromo-8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.92 (br, 1H), 8.42 (s, 1H), 7.50 (d, 2H),6.90 (d, 2H), 5.90 (m, 1H), 4.10 (m, 2H), 2.61 (m, 2H), 2.60 (s, 3H),2.41 (m, 4H), 2.20 (m, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.60 (m, 6H),1.40 (m, 2H); MS (EI) for C₂₆H₃₂BrN₅O₂: 527.86 (M+H).

Example 58

8-Cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.92 (bs, 1H), 8.42 (s, 1H), 7.51 (s, 1H),7.50 (d, 2H), 6.91 (s, 1H), 6.90 (d, 2H, 5.90 (m, 1H), 4.10 (m, 2H),2.61 (m, 5H), 2.41 (m, 4H), 2.20 (m, 2H), 1.98 (m, 2H), 1.90 (m, 2H),1.60 (m, 2H), 1.42 (m, 4H), 1.40 (m, 2H); MS (EI) for C₂₉H₃₅N₇O₂: 514.2(M+H).

Example 596-Acetyl-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of6-bromo-8-ethyl-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-onefrom above (502 mg, 1.46 mmol) and 4-(4-ethylpiperazin-1-yl)aniline(3.45 g, 16.8 mmol) were heated (the neat mixture melted upon heating)at 170° C. for ten minutes and cooled to room temperature. The reactionwas partitioned between aqueous and organic layers with ethyl acetateand H₂O. The organic layer was dried with anhydrous magnesium sulfate,filtered and evaporated, and directly applied to prep-LC to provideproduct (320 mg, 46.5% yield); 471.0 [M+H].

To a solution of6-bromo-8-ethyl-2-(4-(1-ethylpiperidin-4-yl)phenylamino)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(310 mg, 0.66 mmol) in 10 mL of toluene was added Pd(PPh₃)₄ (762 mg, 10mol %) and tributyl-1-ethylvinyltin (357 mg, 1.03 mmol). The reactionmixture was heated to 120° C. and stirred for 3 h, and then cooled toroom temperature, and evaporated to dryness. The residue was directlysubjected to prep-LC to give6-Acetyl-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(120.0 mg, 41.9% yield): ¹H NMR (400 MHz, CH₃OH-d₄): δ 8.60 (s, 1H),7.60 (d, 2H), 6.98 (d, 2H), 4.45 (q, 2H), 3.30 (s, 3H), 3.20 (m, 4H),2.70 (m, 4H), 2.61 (s, 3H), 2.50 (q, 2H), 1.30 (t, 3H), 1.18 (t, 3H); MS(EI) for C₂₄H₃₀N₆O₂: 435.0 (MH⁺).

Intermediate 72-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) andbenzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). Thereaction was heated to 80° C. and allowed to run for 12 h. Upon coolingto room temperature, a white precipitate formed which was collected byvacuum filtration. The solid was recrystallized from acetone: hexanes toafford N⁴-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as awhite solid.

Iodine (3.04 g, 12.0 mmol) was added to a solution ofN⁴-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) inanhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to roomtemperature overnight. After 12 hours, an additional 0.5 equiv of iodinewas added, and the reaction warmed to 50° C. After four hours, thereaction was cooled to room temperature and concentrated in vacuo. Theresidue was diluted with ethyl acetate (200 mL) and washed with 10%NaHSO₃ (200 mL). The aqueous phase was separated and washed once morewith ethyl acetate (200 mL). The organic phases were combined, washedwith brine, separated and dried over Na₂SO₄, The filtrate wasconcentrated in vacuo to afford the productN⁴-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).

Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension ofN⁴-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol),ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh₃)₄ (629 mg, 0.545 mmol)in anhydrous DMF (20 mL). The reaction was heated to 95° C. undernitrogen. After 24 h, the reaction was allowed to cool to roomtemperature and concentrated in vacuo. The residue was poured into a 10%solution of LiCl and washed with ethyl acetate (100 mL). The organicphase was separated and washed with brine, separated and dried overNa₂SO₄. The filtrate was concentrated in vacuo and purified on SiO₂ (3:2methylene chloride:ethyl acetate) to afford(E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate(0.954 g, 28% yield) as a light yellow solid.

2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-oneDiazabicyclo[5.4.0]undec-7-ene (DBU) (1.83 mL, 12.2 mmol) was added to aflask charged with(E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate(0.954 g, 3.05 mmol) and the reaction refluxed at 160° C. under anitrogen atmosphere. After 20 hours, the reaction was cooled to roomtemperature and concentrated in vacuo. Purification on SiO₂ (1:1methylene chloride:ethyl acetate) afforded the product (0.508 g, 62%yield) as an off-white solid.

Bromine (72 μL, 1.40 mmol) was added to a suspension of2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.340g, 1.27 mmol) in methylene chloride (20 mL) at 0° C. The reaction wasallowed to warm to room temperature over one hour and the resultingprecipitate collected by vacuum filtration to afford2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.435 g, 99% yield) after drying. The yellow solid was used in the nextstep without further purification.

A 10:1 solution of dioxane and water (11 mL) was added to a flaskcharged with2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.435 g, 1.27 mmol), 1H-pyrazole-5-boronic acid (0.284 g, 2.54 mmol),Pd(PPh₃)₄ (0.073 mg, 0.063 mmol), and K₂CO₃ (0.527 g, 3.81 mmol). Theflask was flushed with nitrogen and fitted with a reflux condenser andheated to 110° C. After 12 h the reaction was cooled to room temperatureand diluted with ethyl acetate (100 mL) and washed with water. Theaqueous phase was acidified to pH 1.0 and washed with ethyl acetate (100mL). The organic phases were combined and washed with brine, separatedand dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas precipitated with ethyl acetate to give2-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.062 g, 15% yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d6): δ13.10 (bs, 1H), 12.93 (bs, 1H), 8.47 (s, 1H), 7.76 (bs, 1H), 7.51 (bs,1H), 7.28 (m, 5H), 6.97 (s, 1H), 5.55 (s, 2H), 2.55 (bs, 3H); MS (EI)for C_(18H16)N₆O: 333.1 (MH⁺).

Intermediate 82-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one

A 3:1 solution of dioxane and water (4 mL) was added to a flask chargedwith 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.140 g, 0.495 mmol) from above, 4-methylthiophene-3-boronic acid(0.140 g, 0.989 mmol), Pd(PPh₃)₄ (0.057 mg, 0.050 mmol), and K₂CO₃(0.205 g, 1.48 mmol). The flask was flushed with nitrogen and fittedwith a reflux condenser and heated to 100° C. After 12 hours thereaction was cooled to room temperature and diluted with ethyl acetate(70 mL) and washed with water. The aqueous phase was separated andwashed with an additional amount of ethyl acetate (70 mL). The organicphases were combined and washed with brine, separated and dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified onSiO₂ (1:1 methylene chloride:ethyl acetate) to give2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.081 g, 55% yield) as an off-white solid: ¹H NMR (400 MHz, DMSO-d₆): δ7.84 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.19 (m, 3H), 4.32 (q, J=8.0 Hz,2H), 2.52 (s, 3H), 2.11 (bs, 3H), 1.19 (t, J=8.0 Hz, 3H); MS (EI) forC₁₅H₁₆N₄OS: 301.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Intermediate 9

2-Amino-8-ethyl-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.11 (dd, J=2.8, 1.2 Hz, 1H), 7.95 (s, 1H),7.51 (dd, J=5.2, 1.2 Hz, 1H), 7.37 (dd, J=4.8, 3.2 Hz, 1H), 5.21, (bs,2H), 4.48 (q, J=6.8 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); MS(EI) for C₁₄H₁₄N₄OS: 287.0 (MH⁺).

Intermediate 10

2-Amino-8-ethyl-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.47 (bs, 1H), 7.85 (s, 1H), 7.49 (t, J=1.6Hz, 1H), 6.77 (dd, J=2.0, 0.8 Hz, 1H), 5.19, (bs, 2H), 4.48 (q, J=6.8Hz, 2H), 2.64 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); MS (EI) for C₁₄H₁₄N₄O₂:271.1 (MH⁺).

Intermediate 11

2-Amino-6-(3,5-dimethylisoxazol-4-yl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.62 (s, 1H), 5.27, (bs, 2H), 4.44 (q, J=7.2Hz, 2H), 2.59 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), 1.31 (t, J=6.8 Hz,3H); MS (EI) for C₁₅H₁₇N₅O₂: 300.1 (MH⁺).

Intermediate 12

2-Amino-8-ethyl-6-isoxazol-4-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 9.36 (s, 1H), 8.71 (s, 1H), 7.91 (s, 1H),5.30, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.32 (t, J=6.8 Hz,3H); MS (EI) for C₁₃H₁₃N₅O₂: 272.0 (MH⁺).

Intermediate 13

2-Amino-8-ethyl-6-furan-2-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.37(d, J=3.6 Hz, 1H), 6.53 (dd, J=3.6, 2.0 Hz 1H), 5.21, (bs, 2H), 4.48 (q,J=7.2 Hz, 2H), 2.66 (s, 3H), 1.32 (t, J=6.8 Hz, 3H); MS (EI) forC₁₄H₁₄N₄O₂: 271.0 (MH⁺).

Intermediate 14

5-(2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-a]pyrimidin-6-yl)thiophene-2-carbonitrile:¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.55(d, J=4.4 Hz, 1H), 5.33, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.68 (s, 3H),1.33 (t, J=6.8 Hz, 3H); MS (EI) for C₁₅H₁₃N₅OS: 312.0 (MH⁺).

Intermediate 15

2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 12.88 (s, 1H), 8.38 (s, 1H), 8.17 (s, 2H),7.10 (bs, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.20 (t, J=7.2 Hz,3H); MS (EI) for C₁₃H₁₄N₆O: 271.0 (MH⁺).

Intermediate 16

2-Amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.94 (s, 1H), 7.94 (d, J=3.2 Hz, 1H), 7.46(d, J=3.2 Hz, 1H), 5.34 (bs, 2H), 4.54 (q, J=7.2 Hz, 2H), 2.73 (s, 3H),1.35 (t, J=7.2 Hz, 3H); MS (EI) for C₁₃H₁₃N₅OS: 288.0 (MH⁺).

Intermediate 17

2-Amino-8-ethyl-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s, 1H), 7.20 (bs, 2H), 6.81 6.11 (dd,J=3.6, 2.0 Hz, 1H), 6.02 (t, J=3.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.49(s, 3H), 2.52 (s, 3H), 1.19 (t, J=7.2 Hz, 3H); MS (EI) for C₁₅H₁₇N₅O:284.1 (MH⁺).

Intermediate 18

2-Amino-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one: ¹HNMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.65 (d, J=6.8 Hz, 2H), 7.43 (d,J=7.2 Hz, 2H), 7.36 (d, J=7.2 Hz, 1H), 5.24 (bs, 2H), 4.47 (q, J=7.2 Hz,2H), 2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₆N₄O: 281.2(MH⁺)

Intermediate 19

2-Amino-8-ethyl-6-(4-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 6.96(d, J=8.8 Hz, 2H), 5.17 (bs, 2H), 4.47 (q, J=6.8 Hz, 2H), 3.85 (s, 3H),2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C₁₇H₁₈N₄O₂: 311.2(MH⁺)

Intermediate 20

2-Amino-8-ethyl-6-(2-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (m, 1H), 7.36 (m, 2H), 7.01 (m, 2H),5.20 (bs, 2H), 4.45 (m, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 1.31 (m, 3H),MS (EI) for C₁₇H₁₈N₄O₂: 311.2 (MH⁺)

Intermediate 21

2-Amino-6-(4-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.39(d, J=8.8 Hz, 2H), 5.23 (bs, 2H), 4.46 (q, J=7.2 Hz, 2H), 2.61 (s, 3H),1.31 (d, J=6.8 Hz, 3H), MS (EI) for C₁₆H₁₅CN₄O: 315.1 (MH⁺)

Intermediate 22

2-Amino-6-(3-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.66 (m, 1H), 7.56 (m, 1H),7.35 (m, 2H), 5.25 (bs, 2H), 4.46 (q, J=5.6 Hz, 2H), 2.61 (s, 3H), 1.31(d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₅ClN₄O: 315.1 (MH⁺)

Intermediate 23

2-Amino-6-(2-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (m, 2H),7.38 (m, 1H), 7.333 (m, 1H), 5.22 (bs, 2H), 4.46 (q, J=6.8 Hz, 2H), 2.57(s, 3H), 1.31 (d, J=6.8 Hz, 3H), MS (EI) for C₁₆H₁₅CN₄O: 315.1 (MH⁺)

Intermediate 24

2-Amino-6-(2,4-dichlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.77 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H),7.32 (m, 1H), 5.24 (bs, 2H), 4.45 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.30(d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₄Cl₂N₄O: 349.1 (MH⁺)

Intermediate 25

2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 12.97 (bs, 1H), 8.37 (s, 1H), 7.60 (bs,1H), 7.24 (bs, 2H), 6.95 (s, 1H), 4.33 (q, 2H), 2.55 (s, 3H), 1.81 (t,3H); MS (EI) for C₁₃H₁₄N₆O: 271.3 (MH⁺).

Intermediate 26

2-Amino-8-ethyl-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 7.85-7.13 (m, 5H), 4.37 (q,J=7.2 Hz, 2H), 2.62 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) forC₁₄H₁₄N₄OS: 287.1 (MH⁺).

Intermediate 27

2-Amino-8-ethyl-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (s, 1H), 7.76-7.22 (m, 6H), 4.34 (q,J=7.2 Hz, 2H), 2.56 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS (EI) forC₁₆H₁₅FN₄O: 299.2 (MH⁺).

Intermediate 28

2-Amino-8-ethyl-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (s, 1H), 7.61-7.44 (m, 3H), 7.29 (bs,2H), 7.20-7.15 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.20 (t,J=7.2 Hz, 3H); MS (EI) for C₁₆H₁₅FN₄O: 299.2 (MH⁺).

Intermediate 29

2-Amino-8-ethyl-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (s, 1H), 7.50-7.23 (m, 6H), 4.32 (q,J=6.8 Hz, 2H), 2.52 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (EI) forC₁₆H₁₅FN₄O: 299.2 (MH⁺).

Intermediate 30

Methyl3-(2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)benzoate:¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (s, 1H), 8.06 (s, 1H), 7.95-7.55 (m,3H), 7.28 (bs, 1H), 4.35 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 2.58 (s, 3H),1.21 (t, J=6.8 Hz, 3H); MS (EI) for C_(18H18)N₄O₃: 339.2 (MH⁺).

Intermediate 31

2-Amino-8-ethyl-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 7.65-7.30 (m, 5H), 4.31 (q,J=7.2 Hz, 2H), 2.50 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (EI) forC₁₄H₁₄N₆O: 283.2 (MH⁺).

Example 608-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a pressure tube charged with2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (500mg, 1.77 mmol) and 2-tributylstannylthiazole (793 mg, 3.54 mmol) in drytoluene (6.0 mL) was added Pd(PPh₃)₄ (204 mg, 0.177 mmol). The pressuretube was sealed under nitrogen and heated to 110° C. After 12 h, thereaction was cooled to room temperature and concentrated in vacuo. Theresidue was redissolved in ethyl acetate and 40% KF on alumina (2 g)added. After 30 minutes, the alumina was filtered and the filtratewashed consecutively with 1M aqueous KF and brine. The organic layer wasseparated and dried over Na2SO4, filtered and concentrated in vacuo. Theresidue was triturated with methylene chloride and hexanes to provide2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(178 mg, 35% yield) as a yellow solid. MS calculated for C₁₃H₁₃N₅OS287.346, MS (EI) observed 288.0 (MH⁺).

Acetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (45 mg,0.098 mmol) was added to pressure tube charged with2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(141 mg, 0.490 mmol),tert-butyl-4-(4-iodophenyl)tetrahydro-1(2H)pyrazinecarboxylate (209 mg,0.539 mmol), and sodium tert-pentoxide (135 mg, 1.23 mmol) in drytoluene (1.5 mL). The pressure was capped under nitrogen and heated to70° C.). After 60 hours, the reaction was cooled to room temperature andfiltered through a pad of Celite. The filtrate was purified on silicagel (1:1 hexanes:ethyl acetate) to provide the product, tert-butyl4-(4-(8-ethyl-4-methyl-7-oxo-6-(thiazol-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate(99 mg, 34% yield).

A solution of 4M HCl in doxane (3 mL) was added to a solution oftert-butyl4-(4-(8-ethyl-4-methyl-7-oxo-6-(thiazol-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate(99 mg, 0.181 mmol) in anhydrous methanol. After one h, a precipitateformed which was collected by vacuum filtration and identified as8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(60 mg, 74% yield) as the HCl salt; MS calculated for C₂₃H₂₅N₇OS.HCl:447.5645, MS (EI) observed 448.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents,8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-onewas prepared. MS calculated for C₂₆H₂₉N₇OS.TFA: 487.6291, MS (EI)observed 488.0 (MH⁺).

Intermediate 322-Amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

A solution of potassium hydroxide (0.139 g, 2.48 mmol) in absoluteethanol (3.0 mL) was added to a pressure tube charged with4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.229g, 1.08 mmol), prepared using procedures similar to those described forIntermediate 1, and 2-(1H-imidazol-5-yl)acetonitrile (0.174 g, 162 mmol)and heated to 70° C. After 12 h, the reaction was allowed to cool toroom temperature and concentrated in vacuo affording8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imineas a solid. The product was used in the subsequent step without furtherpurification.

Acetic anhydride (15.0 mL) was added to a flask charged with crude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imineand heated to 100° C. After 30 minutes, the reaction was allowed to coolto room temperature and concentrated in vacuo. The acetylated residuewas then treated with 6 N HCl (16 mL) and heated to 95° C. for 30minutes then transferred to a large flask. A saturated solution ofNaHCO₃ (150 mL) was added at 0° C. to about pH=8.0. The aqueous phasewas washed thrice with ethyl acetate (100 mL) and the organic layerscombined, then washed with brine and dried over Na₂SO₄. The drying agentwas filtered off and the organic layers were concentrated in vacuo toafford crude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onewhich was used in the subsequent step without further purification.

3-Chloroperbenzoic acid (0.299 g, 1.73 mmol) was added to a solution ofcrude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.260 g, 0.866 mmol) in dichloromethane (10.0 mL) at room temperature.After 1.5 h, the reaction was diluted with dichloromethane (50 mL) andwashed twice with saturated NaHCO₃, followed by brine. The organic phasewas separated and dried over Na₂SO₄, filtered, and concentrated invacuo. The corresponding sulfone was used in the subsequent step withoutfurther purification.

Concentrated aqueous ammonium hydroxide (400 μL) was added to a solutionof the sulfone in dioxane (10 mL) at 0° C. The reaction flask sealed,and allowed to warm to room temperature upon standing overnight. Thereaction was concentrated in vacuo and purified on reverse phase HPLC(acetonitrile: water 0.1% TFA, 20-60% gradient). The fractionscontaining product were collected and concentrated to one half volumeand poured into saturated NaHCO₃ (50 mL). The aqueous phase was washedtrice with ethyl acetate (50 mL) and dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was triturated with methylenechloride and ethyl acetate to afford2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(29 mg, 12% yield) as a light yellow solid: ¹H NMR (400 MHz, CH₃OH-d₄):δ 8.52 (bs, 1H), 7.88 (bs, 1H), 7.76 (s, 1H), 4.30 (q, J=6.8 Hz, 2H),2.65 (s, 3H), 1.29 (t, J=6.8 Hz, 3H); MS (EI) for C₁₃H₁₄N₆O: 271.0(MH⁺).

Intermediate 332-Amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Trimethylsilylethyne (1.44 mL, 10.2 mmol) was added to a pressure tubecharged with2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.58g, 5.59 mmol) from above, CuI (0.053 g, 0.279 mmol), and PdCl₂(PPh₃)₂(0.211 g, 0.279 mmol) in triethylamine (20 mL). The pressure tube wassealed under nitrogen and heated to 50° C. 96 h. The reaction was cooledto room temperature and poured into a saturated solution of NaHCO₃ (150mL), then washed four times with ethyl acetate (50 mL). The organiclayers were pooled and dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified on SiO₂ (2:1, methylene chloride:ethylacetate) to afford2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one(1.09 g, 65% yield) as an off white solid.

Potassium carbonate (1.00 g, 7.28 mmol) was added to a flask chargedwith2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one(1.09 g, 3.64 mmol) in anhydrous methanol (15 mL). The reaction wasstirred at room temperature under nitrogen for 16 h. The reaction wasconcentrated to one half volume and the yellow precipitate collected byvacuum filtration to afford2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

Anhydrous DMF (5.0 mL) was added to a flask charged with2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammoniumchloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogenand heated to 120° C. After 48 h, the reaction was cooled to roomtemperature and concentrated in vacuo. The residue was purified onreverse phase HPLC (acetonitrile: water 0.1% TFA, 20-60% gradient). Thefractions containing product were collected and concentrated to one halfvolume and poured into saturated NaHCO₃ (50 mL). The aqueous phase waswashed trice with ethyl acetate (50 mL) and dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was triturated with methylenechloride and ethyl acetate to afford2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(14 mg, 6% yield) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆): δ8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H),2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C_(12H13)N₇O: 272.0(MH⁺).

Intermediate 342-Amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Potassium carbonate (0.539 g, 3.90 mmol) was added to a suspension of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.413g, 1.95 mmol) from above, and malononitrile (0.194 g, 2.93 mmol) inabsolute ethanol (15.0 mL) and heated to 70° C. After one h, thereaction was allowed to cool to room temperature and concentrated invacuo. The residue was diluted with ethyl acetate (50 mL) and washedwith saturated NaHCO₃ (50 mL), and brine. The organic phase wasseparated and concentrated in vacuo. The residue was precipitated withethyl acetate and hexanes to give8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrileas a brown solid that was used in the subsequent step without furtherpurification.

Acetic anhydride (10.0 mL) was added to a flask charged with8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.506 g, 1.95 mmol) and heated to 100° C. After one h, the reaction wasallowed to cool to room temperature and concentrated in vacuo. Theacetylated residue was then treated with 6 N HCl (40 mL) and heated to95° C. for one hour then transferred to a large flask. A saturatedsolution of NaHCO₃ (500 mL) was added slowly at 0° C. until a pH 8.0 wasachieved. The aqueous phase was washed thrice with ethyl acetate (100mL) and the organic layers combined, then washed with brine and driedover Na₂SO₄. The drying agent was filtered and concentrated in vacuo toafford crude8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewhich was used in the subsequent step without further purification.

3-Chloroperbenzoic acid (1.00 g, 5.85 mmol) was added to a solution ofcrude8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.507 g, 1.95 mmol) in dichloromethane (30.0 mL) at room temperature.After 2.5 hours, the reaction was diluted with dichloromethane (50 mL)and washed twice with saturated NaHCO₃, followed by brine. The organicphase was separated and dried over Na₂SO₄, filtered, and concentrated invacuo.2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewas used in the subsequent step without further purification.

Ammonium hydroxide (500 μL) was added to a solution of the above sulfonein dioxane (10 mL) at 0° C. The reaction flask sealed, and allowed towarm to room temperature upon standing overnight. The reaction wasconcentrated in vacuo triturated with ethyl acetate to afford theproduct which was used in the subsequent step without furtherpurification.

Tributyltin azide (660 μL, 2.41 mmol) was added to a flask charged with2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.184 g, 0.803 mmol) in anhydrous toluene (5.0 mL). The reaction wasfitted with a reflux condenser and heated to 140° C. under a nitrogenatmosphere. After 20 h, the reaction was cooled to room temperature andthe precipitate collected by vacuum filtration and washed with absoluteethanol to give2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(98 mg, 45% yield) as a light brown solid: ¹H NMR (400 MHz, 20% DCl inD₂O): δ 6.97 (s, 1H), 2.42 (q, J=7.2 Hz, 2H), 0.953 (s, 3H), −0.73 (t,J=7.2 Hz, 3H); MS (EI) for C₁₁H₁₁N₈O: 271.0 (MH⁺).

Intermediate 358-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of8-(3-methoxypropyl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.36 g, 1.29 mmol), prepared using procedures similar to thosedescribed in Example 1, dichloromethane (10 mL), and 77%3-chloroperbenzoic acid with water (0.723 g, 3.23 mmol) was stirred for1 h. The mixture was diluted with dichloromethane, washed with sat.sodium bicarbonate (3 times), brine, dried over sodium sulfate, and DCMwas removed under reduced pressure to give8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one.

Intermediate 36

A mixture of 2,4-dichloro-6-methylpyrimidine (Aldrich, 5 g, 30 mmol),cyclohexylamine (3 g, 30 mmol) and DIEA (10 mL) was stirred at 80° C.for 12 h. The volatile material was removed under reduced pressure. Theresidue was loaded on a silica gel column, and was eluted withhexanes/ethyl acetate (3:1).8-cyclohexyl-2-(ethylamino)-4-methyl-6-(thiopheN-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-onewas obtained as colorless oil (2.8 g, 41% yield).

BIOLOGICAL EXAMPLES Biological Example 1 PI3Kalpha Luciferase-CoupledChemiluminescence Assay Protocol

PI3Kα activity is measured as the percent of ATP consumed following thekinase reaction using luciferase-luciferin-coupled chemiluminescence.Reactions were conducted in 384-well white, medium binding microtiterplates (Greiner). Kinase reactions were initiated by combining testcompounds, ATP, substrate (PIP2), and kinase in a 20 μL volume in abuffer solution. The standard PI3Kalpha assay buffer is composed 50 mMTris, pH 7.5, 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT and 0.03% CHAPS. Thestandard assay concentrations for enzyme, ATP, and substrate are 0.5-1.1nM, 1 μM, and 7.5 μM, respectively. The reaction mixture was incubatedat ambient temperature for approximately 2 h. Following the kinasereaction, a 10 μL aliquot of luciferase-luciferin mix (PromegaKinase-Glo) was added and the chemiluminescence signal measured using aVictor2 plate reader (Perkin Elmer). Total ATP consumption was limitedto 40-60% and IC₅₀ values of control compounds correlate well withliterature references.

Certain compounds of the invention were tested in this assay anddemonstrated the ability to bind to PI3K. For example, in one embodimentof the invention, the PI3K inhibitor is selected from the compounds inTable 1 having a PI3K-binding affinity of about 9 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 5 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 3 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 1.5 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 1 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.6 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.3 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.2 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.1 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.04 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.020 μM or less.

Biological Example 2

Phospho AKT assay PC3 cells were seeded on 6-well plates at 150,000cells/well. Cells were cultured for 3 days, then treated with compoundsin serum-free medium for 3 hr. EGF (100 ng/mL) was added for the last 10min. Cells were lysed in TENN buffer. Phospho T308 Akt and total Aktwere quantified by ELISA performed according to the Biosource assayprotocol. The readings of phospho Akt were normalized to total Aktreadings.

Biological Example 3 Phospho S6 assay

PC3 cells were seeded on 96-well plates at 8,000 cells/well. For eachexperiment, cells were seeded and treated in duplicated plates: oneplate for phospho S6 CellELISA, and one plate for total S6 CellELISA.Cells were cultured on the plates for 3 days, then treated withcompounds in serum-free medium for 3 hr in triplicate. Cells were fixedwith 4% formaldehyde, quenched with 0.6% H₂O₂, blocked with 5% BSA,incubated with either phospho S6 antibody or total S6 antibodyovernight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, anddeveloped in chemiluminescent substrate.

Biological Example 4 PIP3 Assay

MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, andthen treated with compounds for 20 minutes. In the last 2 minutes of theincubation with the compounds, EGF (100 ng/mL) was added to stimulatethe production of PIP3. The medium was aspirated and the cells werescraped with 10% trichloroacetic acid. The lipids were extracted fromthe pellet after the cell lysates were centrifuged. PIP3 in the cellularlipid extraction was quantified with the AlphaScreen assay in whichGrp1-PH is used as the PIP3 specific probe. The amount of cellular PIP3was calculated from the standard curve of diC₈ PI (3,4,5) P3.

Biological Example 5-10 In Vivo Models

Female and male athymic nude mice (NCr) 5-8 weeks of age and weighingapproximately 20 g were used in the following model. Prior to initiationof a study, the animals were allowed to acclimate for a minimum of 48 h.During these studies, animals were provided food and water ad libitumand housed in a room conditioned at 70-75° F. and 60% relative humidity.A 12 h light and 12 h dark cycle was maintained with automatic timers.All animals were examined daily for compound-induced or tumor-relateddeaths.

PC-3 human prostate adenocarcinoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 20% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 3×10⁶ cells (passage 13, 99% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted subcutaneouslyinto the hindflank of 5-8 week old male nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily.

U-87 MG human glioblastoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 2×10⁶ cells (passage 5, 96% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted intradermally intothe hindflank of 5-8 week old female nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily.

A549 human lung carcinoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 10×10⁶ cells (passage 12, 99% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted intradermally intothe hindflank of 5-8 week old female nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily.

A2058 human melanoma cells were cultured in vitro in DMEM (Mediatech)supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 3×10⁶ cells (passage 3, 95% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice. A transponderwas implanted in each mouse for identification, and animals weremonitored daily for clinical symptoms and survival. Body weights wererecorded daily.

WM-266-4 human melanoma cells were cultured in vitro in DMEM (Mediatech)supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 3×10⁶ cells (passage 5, 99% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice. A transponderwas implanted in each mouse for identification, and animals weremonitored daily for clinical symptoms and survival. Body weights wererecorded daily.

For subcutaneous or intradermal tumors, the mean tumor weight of eachanimal in the respective control and treatment groups was determinedtwice weekly during the study. Tumor weight (TW) was determined bymeasuring perpendicular diameters with a caliper, using the followingformula:

tumor weight(mg)=[tumor volume=length(mm)×width²(mm²)]/2

These data were recorded and plotted on a tumor weight vs. dayspost-implantation line graph and presented graphically as an indicationof tumor growth rates. Percent inhibition of tumor growth (TGI) isdetermined with the following formula:

$\left( {1 - \left( \frac{\left( {X_{f} - X_{0}} \right)}{\left( {Y_{f} - X_{0}} \right)} \right)} \right)*100$

-   -   where X₀=average TW of all tumors on group day    -   X_(f)=TW of treated group on Day f    -   Y_(f)=TW of vehicle control group on Day f        If tumors regress below their starting sizes, then the percent        tumor regression is determined with the following formula:

$\left( \frac{\left( {X_{0} - X_{f}} \right)}{X_{0}} \right)*100$

Tumor size is calculated individually for each tumor to obtain amean±SEM value for each experimental group. Statistical significance isdetermined using the 2-tailed Student's t-test (significance defined asP<0.05).

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containinga compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Ingredient Quantity per tablet, mg compound of this invention 400Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg distilledwater q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 1.2 g sodium acetate buffersolution 0.4 M 2.0 mL HCl (1 N) or NaOH (1 M) q.s. to suitable pH water(distilled, sterile) q.s.to 20 mL

All of the above ingredients, except water, are combined and heated to60-70.degree. C. with stirring. A sufficient quantity of water at60.degree. C. is then added with vigorous stirring to emulsify theingredients, and water then added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition:

Ingredient Quantity per tablet, mg compound of this invention 500Witepsol ® H-15 balance

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specificembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention. It will be obvious to one of skill inthe art that changes and modifications may be practiced within the scopeof the appended claims. Therefore, it is to be understood that the abovedescription is intended to be illustrative and not restrictive. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled. All patents,patent applications and publications cited in this application arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual patent, patent application orpublication were so individually denoted.

1. A compound of Formula I:

or a single stereoisomer or mixture of stereoisomers thereof andoptionally as a pharmaceutically acceptable salt or solvate thereof,wherein R¹ is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; X is —NR³—; R³ is hydrogen; R⁴ isoptionally substituted alkyl; R⁵ is hydrogen; R⁶ is acyl; and R^(2a) isR^(2a) where R^(2a) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, orheterocycloalkyl, where the aryl, cycloalkyl, and heterocycloalkyl,either alone or as part of another group within R^(2a), are optionallysubstituted with 1, 2, 3, 4, or 5 R⁸ groups; or R⁶ is phenyl orheteroaryl where the phenyl and heteroaryl are optionally substitutedwith 1, 2, 3, 4, or 5 R⁹ groups; and R² is R^(2b) where R^(2b) is aryl,arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl, and where the aryl, cycloalkyl, andheterocycloalkyl, either alone or as part of another group withinR^(2b), are optionally substituted with 1, 2, 3, 4, or 5 R⁸ groups; eachR⁸, when present, is independently hydroxy, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, alkoxyalkyl, alkoxycarbonyl, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,alkoxyalkylaminoalkyl, heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkylalkyloxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl and where the cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, each either alone or as part ofanother group within R⁸, are independently optionally substituted with1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy,alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl,alkoxycarbonyl, and arylalkyl; and each R⁹, when present, isindependently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, amino,alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, cyano,alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy,heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, each either alone or as part ofanother group within R⁹, are independently optionally substituted with1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy,alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino.
 2. The Compoundof claim 1 where R¹ is alkyl or cycloalkyl; X is —NH—; R⁴ is alkyl; R⁵is hydrogen; and R⁶ is acyl; and R² is R^(2a) where R^(2a) is aryl wherethe aryl is optionally substituted with one R⁸ group; or R⁶ is phenyl orheteroaryl where the phenyl and heteroaryl are optionally substitutedwith one or two R⁹ groups; and R² is R^(2b) where R^(2b) is aryl,arylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, andwhere the aryl, cycloalkyl, and heterocycloalkyl, either alone or aspart of another group within R^(2b), are optionally substituted with oneor two R⁸ groups; each R⁸, when present, is independently halo, hydroxy,alkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminoalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, heteroaryl, heterocycloalkyl,or heterocycloalkylalkyloxy, and where the heterocycloalkyl, eitheralone or as part of another group within R⁸, is optionally substitutedwith alkyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl; andeach R⁹, when present, is independently halo, alkyl, haloalkyl, alkoxy,aryl, arylalkyl, cyano, or alkoxycarbonyl; or a single stereoisomer ormixture of stereoisomers thereof and optionally as a pharmaceuticallyacceptable salt or solvate thereof.
 3. The Compound of claim 1 where R¹is alkyl or cycloalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 4. The Compound of claim 1 where R¹ iscyclopentyl; or a single stereoisomer or mixture of stereoisomersthereof and optionally as a pharmaceutically acceptable salt or solvatethereof.
 5. The Compound of claim 1 where R⁴ is methyl; or a singlestereoisomer or mixture of stereoisomers thereof and optionally as apharmaceutically acceptable salt or solvate thereof.
 6. The Compound ofclaim 1 where R⁶ is acyl and R^(2a) is aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, or heterocycloalkyl, where the aryl, cycloalkyl, andheterocycloalkyl, either alone or as part of another group withinR^(2a), are optionally substituted with 1, 2, or 3 R⁸ groups; or asingle stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 7. TheCompound of claim 6 where R⁶ is acetyl and R^(2a) is phenyl optionallysubstituted with one R⁸ where the R⁸ is heterocycloalkyl optionallysubstituted with alkyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, orarylalkyl; or a single stereoisomer or mixture of stereoisomers thereofand optionally as a pharmaceutically acceptable salt or solvate thereof.8. The Compound of claim 1 where R⁶ is phenyl or heteroaryl where thephenyl and heteroaryl are optionally substituted with one or two R⁹groups; and R^(2b) is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl, and where the aryl,cycloalkyl, and heterocycloalkyl, either alone or as part of anothergroup within R^(2b), are optionally substituted with one or two R⁸groups; or a single stereoisomer or mixture of stereoisomers thereof andoptionally as a pharmaceutically acceptable salt or solvate thereof. 9.The Compound of claim 8 where R^(2b) is phenyl optionally substitutedwith one R⁸ where the R⁸ is heterocycloalkyl optionally substituted withalkyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl; or asingle stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 10. TheCompound of claim 1 where R⁶ is phenyl optionally substituted with oneor two R⁹ group(s) where each R⁹, when present, is independently halo,alkoxy, or haloalkyl; R^(2b) is aryl optionally substituted with one ortwo R⁸; and each R⁸, when present, is independently halo, hydroxy,alkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminoalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, heteroaryl, heterocycloalkyl,or heterocycloalkylalkyloxy and where the heterocycloalkyl in R⁸, eitheralone or as part of heterocycloalkylalkyloxy, is optionally substitutedwith alkyl, alkoxycarbonyl, or arylalkyl; or a single stereoisomer ormixture of stereoisomers thereof and optionally as a pharmaceuticallyacceptable salt or solvate thereof.
 11. The Compound of claim 10 whereR^(2b) is phenyl optionally substituted with one R⁸ where the R⁸ isheterocycloalkyl optionally substituted with alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl; or a single stereoisomer or a mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 12. The Compound of claim 1 where R⁶ is phenyloptionally substituted with one or two R⁹ group(s) where each R⁹, whenpresent, is independently halo, alkoxy, or haloalkyl; R^(2b) isheterocycloalkylalkyl where the heterocyloalkyl is optionallysubstituted with one R⁸ where the R⁸ is alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 13. The Compound of claim 1 where R⁶ is apyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl optionally substitutedwith one or two R⁹ group(s); or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 14. The Compound of claim 1 where R⁶ ispyrazinyl, pyrimidinyl, or pyridazinyl optionally substituted with oneor two R⁹ group(s); or a single stereoisomer or mixture of stereoisomersthereof and optionally as a pharmaceutically acceptable salt or solvatethereof.
 15. The Compound of claim 13 where R^(2b) is phenyl optionallysubstituted with one R⁸ where the R⁸ is heterocycloalkyl optionallysubstituted with alkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl; ora single stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 16. TheCompound of claim 14 where R^(2b) is phenyl optionally substituted withone R⁸ where the R⁸ is heterocycloalkyl optionally substituted withalkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl; or a singlestereoisomer or mixture of stereoisomers thereof and optionally as apharmaceutically acceptable salt or solvate thereof.
 17. The Compound ofclaim 1 where R⁶ is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl,each of which is optionally substituted with one R⁹ where the R⁹, whenpresent, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo; or asingle stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 18. Thecompound of claim 17 where R⁶ is pyrazol-3-yl, pyrazol-4-yl,pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl,thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl,pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl,each of which is optionally substituted with one R⁹ where the R⁹, whenpresent, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo; or asingle stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 19. TheCompound of claim 17 where R⁶ is thien-2-yl, thien-3-yl, furan-2-yl,furan-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, orthiazol-2-yl, each of which is optionally substituted with one R⁹ wherethe R⁹, when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl,or halo; or a single stereoisomer or mixture of stereoisomers thereofand optionally as a pharmaceutically acceptable salt or solvate thereof.20. The Compound of claim 17 where R⁶ is thien-2-yl, thien-3-yl,furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, orthiazol-2-yl, each of which is optionally substituted with one R⁹ wherethe R⁹, when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl,or halo; or a single stereoisomer or mixture of stereoisomers thereofand optionally as a pharmaceutically acceptable salt or solvate thereof.21. The Compound of claim 17 where R^(2b) is phenyl optionallysubstituted with one or two R⁸; and each R⁸, when present, isindependently halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino,alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,heteroaryl, heterocycloalkyl, or heterocycloalkylalkyloxy and where theheterocycloalkyl in R⁸, either alone or as part ofheterocycloalkylalkyloxy, is optionally substituted with alkyl,alkylcarbonyl, alkoxycarbonyl, or arylalkyl; or a single stereoisomer ormixture of stereoisomers thereof and optionally as a pharmaceuticallyacceptable salt or solvate thereof.
 22. The Compound of claim 17 whereR^(2b) is phenyl optionally substituted with one R⁸ where the R⁸ isheterocycloalkyl optionally substituted with alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 23. The Compound of claim 17 where R^(2b) isheterocycloalkylalkyl where the heterocyloalkyl is optionallysubstituted with one R⁸ where the R⁸ is alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 24. The Compound of claim 18 where R^(2b) isphenyl optionally substituted with one or two R⁸; and each R⁸, whenpresent, is independently halo, hydroxy, alkoxy, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy,dialkylaminoalkyloxy, heteroaryl, heterocycloalkyl, orheterocycloalkylalkyloxy and where the heterocycloalkyl in R⁸, eitheralone or as part of heterocycloalkylalkyloxy, is optionally substitutedwith alkyl, alkylcarbonyl, alkoxycarbonyl, or arylalkyl; or a singlestereoisomer or mixture of stereoisomers thereof and optionally as apharmaceutically acceptable salt or solvate thereof.
 25. The Compound ofclaim 18 where R^(2b) is phenyl optionally substituted with one R⁸ wherethe R⁸ is heterocycloalkyl optionally substituted with alkyl,alkylcarbonyl, alkoxycarbonyl, or arylalkyl; or a single stereoisomer ormixture of stereoisomers thereof and optionally as a pharmaceuticallyacceptable salt or solvate thereof.
 26. The Compound of claim 25 whereR⁸ is morpholinyl or piperazinyl where the piperazinyl ring isoptionally substituted with methyl, ethyl, isopropyl, acetyl,N-tert-butoxycarbonyl, or benzyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 27. The Compound of claim 18 where R^(2b) isheterocycloalkylalkyl where the heterocyloalkyl is optionallysubstituted with one R⁸ where the R⁸ is alkyl, alkylcarbonyl,alkoxycarbonyl, or arylalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 28. The Compound of claim 27 where R^(2b) ismorpholinylalkyl or piperazinylalkyl and the piperazinyl ring isoptionally substituted with methyl, ethyl, isopropyl,N-tert-butoxycarbonyl, or benzyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 29. The Compound according to claim 1 whereinR^(2b) is phenyl optionally substituted with 1, 2, or 3 R⁹ groups; or asingle stereoisomer or mixture of stereoisomers thereof and optionallyas a pharmaceutically acceptable salt or solvate thereof.
 30. TheCompound of claim 29 where R⁸ is piperazinyl or morpholinyl where thepiperazinyl is optionally substituted with alkyl, alkylcarbonyl,alkoxycarbonyl, or phenylalkyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 31. The Compound of claim 1 where R¹ is alkylor cycloalkyl and R⁴ is methyl; or a single stereoisomer or mixture ofstereoisomers thereof and optionally as a pharmaceutically acceptablesalt or solvate thereof.
 32. The Compound of claim 31 where R⁶ ispyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl,triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which isoptionally substituted with one R⁹ where the R⁹, when present, ismethyl, benzyl, cyano, phenyl, or N-tert-butoxycarbonyl; or a singlestereoisomer or mixture of stereoisomers thereof and optionally as apharmaceutically acceptable salt or solvate thereof.
 33. The Compound ofclaim 32 where R^(2b) is phenyl optionally substituted with one or twoR⁸ where each R⁸, when present, is alkylaminoalkyloxy,dialkylaminoalkyloxy, heterocycloalkyl, or heterocycloalkylalkyloxy andwhere the heterocycloalkyl in R⁸, either alone or as part ofheterocycloalkylalkyloxy, is optionally substituted with alkyl,alkylcarbonyl, alkoxycarbonyl, aryl, or arylalkyl; or a singlestereoisomer or mixture of stereoisomers thereof and optionally as apharmaceutically acceptable salt or solvate thereof.
 34. The Compound ofclaim 1 where R⁴ is methyl and R^(2a) is cycloalkyl, cycloalkylalkyl, orarylalkyl; or a single stereoisomer or mixture of stereoisomers thereofand optionally as a pharmaceutically acceptable salt or solvate thereof.35. The Compound of claim 1 where R⁴ is methyl and R^(2b) is cycloalkyl,cycloalkylalkyl, or arylalkyl; and R⁶ is phenyl or heteroaryl where thephenyl and heteroaryl are optionally substituted with one or two R⁹groups; or a single stereoisomer or mixture of stereoisomers thereof andoptionally as a pharmaceutically acceptable salt or solvate thereof. 36.A compound selected from:6-bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8h)-one;6-bromo-8-ethyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(3-morpholin-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8h)-one;6-bromo-8-ethyl-2-[(2-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one; 6-bromo-8-ethyl-4-methyl-2- {[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3- d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-( {4-[4-(phenylmethyl)piperazin- 1-yl]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino }-6-furan-3 -yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3- d]pyrimidin-7(8h)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8h)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4- methylpyrido[2 ,3 -d]pyrimidin-7(8H)-one; 2-55[4-(4-ethylpiperazin- 1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-[(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,5-difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl }amino)-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one; 6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino }-4-methyl-8-(1- methylethyl)pyrido[2 ,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2 ,3 -d]pyrimidin-7(8H)-one;6-acetyl-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one; 1,1-dimethylethyl4-{4-[(6-bromo-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]phenyl}piperazine- 1-carboxylate6-bromo-8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin- 7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2 3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one; 6-bromo-8-cyclopentyl-4-methyl-2-({4-[(2-piperidin- 1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-(phenylamino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;1,1-dimethylethyl4-(4-{[8-cyclopentyl-4-methyl-7-oxo-6-(1H-pyrazol-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazine-1-carboxylate8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1H-pyrazol-5-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one; 8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-3-yl)pyrido[2 ,3-d]pyrimidin-7(8H)-one;2-(cyclopropylamino)-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-[(cyclopropylmethyl)amino]-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-{[4-(methyloxy)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-[(4-aminophenyl)amino]-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;methyl3-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate methyl4-[(8-cyclopentyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]benzoate 8-cyclopentyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({[4-(4-methylpiperazin-1-yl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-7(8h)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; 2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino }-4-methyl-8-( 1-methylethyl)-6-(1H-pyrazol- 1-yl)pyrido[2,3- d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclohexyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3R)-tetrahydrofuran-3-yl]pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3S)-tetrahydrofuran-3 -yl]pyrido[2,3 -d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-4-methyl-6-(1,3- thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1,3- thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; and8-cyclopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; and optionally as apharmaceutically acceptable salt or solvate thereof.
 37. The Compound ofclaim 1 selected from:8-ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one; 8-ethyl-4-methyl-2-{[4-(4-methylpiperazin- 1-yl)phenyl]amino}-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)-6-(2- thienyl)pyrido[2,3 -d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8h)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-[(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2 ,3-d]pyrimidin-7(8H)- one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,5-difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-acetyl-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8h)-one;8-cyclopentyl-2-[(4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-dpyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-(phenylamino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one; 1,1-dimethylethyl4-(4-{[8-cyclopentyl-4-methyl-7-oxo-6-(1H-pyrazol-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazine-1-carboxylate8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(cyclopropylamino)-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; 2-[(cyclopropylmethyl)amino]-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2 ,3- d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; 2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;8-cyclohexyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-(tetrahydrofuran-3 -yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3R)-tetrahydrofuran-3 -yl]pyrido[2,3 -d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)-8-[(3S)-tetrahydrofuran-3-yl]pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; and8-cyclopentyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one; and optionally as apharmaceutically acceptable salt or solvate thereof.
 38. Apharmaceutical composition which comprises a compound of claim 1 or a ora single stereoisomer or mixture of stereoisomers thereof, optionally asa pharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier, excipient, or diluent.
 39. A methodfor treating a disease, disorder, or syndrome which method comprisesadministering to a patient a therapeutically effective amount of acompound of claim 1 or a single stereoisomer or mixture of stereoisomersthereof, optionally as a pharmaceutically acceptable salt or solvatethereof, or administering to a patient a pharmaceutical compositioncomprising a compound of claim 1 or a single stereoisomer or mixture ofstereoisomers thereof, optionally as a pharmaceutically acceptable saltor solvate thereof, and a pharmaceutically acceptable carrier,excipient, or diluent.
 40. The method of claim 39 where the disease iscancer.
 41. The method of claim 39 where the cancer is breast cancer,colon cancer, rectal cancer, endometrial cancer, gastric carcinoma,glioblastoma, hepatocellular carcinoma, small cell lung cancer,non-small cell lung cancer, melanoma, ovarian cancer, cervical cancer,pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), or thyroid carcinoma.
 42. The methodof claim 39 where the cancer is ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, or glioblastomas.
 43. A method oftreating a disease, disorder, or syndrome which method comprisesadministering to a patient a therapeutically effective amount of acompound of Formula II or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition comprising a compound ofFormula II and a pharmaceutically acceptable carrier, excipient, ordiluent; where the Compound of Formula II is that wherein:

or a single stereoisomer or mixture of stereoisomers thereof, optionallyas a pharmaceutically acceptable salt or solvate thereof, wherein R¹ ishydrogen, optionally substituted alkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heterocycloalkyl, optionallysubstituted heterocycloalkylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; X is S, SO₂, or —NR³—; R² ishydrogen, haloalkyl, optionally substituted alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heterocycloalkyl,optionally substituted heterocycloalkylalkyl, optionally substitutedheterocycloalkyl-aryl- or optionally substituted heteroaryl; R² isoptionally further substituted with one or more R⁸ groups; R³, R^(3a),and R^(3b) are independently hydrogen, optionally substituted alkyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl,optionally substituted heterocycloalkyl or optionally substitutedheteroaryl; R⁴ is hydrogen, halo, haloalkyl, haloalkoxy, —NR^(3a)—,optionally substituted alkyl, optionally substituted C₁-C₆ alkoxy,optionally substituted C₁-C₆ alkoxyalkyl, optionally substitutedaminoalkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; R⁵ is hydrogen,halo, haloalkyl, haloalkoxy, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₁-C₆alkoxyalkyl, optionally substituted aminoalkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted aryl, optionally substitutedaryl C₁-C₆ alkyl or optionally substituted heteroaryl; and R⁶ ishydrogen, halo, haloalkyl, haloalkoxy, —NR^(3b)—, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedC₁-C₆ alkoxyalkyl, optionally substituted acyl, optionally substitutedaminoalkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl;substitutable R⁶ groups are optionally further substituted with 1, 2, 3,4, or 5 R⁹ groups; each R⁸, when present, is independently hydroxy,halo, haloalkyl, haloalkoxy, optionally substituted alkyl, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₁-C₆ alkoxyalkyl,optionally substituted C₁-C₆ alkoxyalkylaminoalkyl, C₁-C₆alkylcarboxyheterocycloalkyl, oxy C₁-C₆alkylheterocycloalkyl, optionallysubstituted aminoalkyl, optionally substituted C₃-C₇ cycloalkyl,optionally substituted aryl, optionally substituted aryl C₁-C₆ alkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁹, when present, is independentlyhalo, haloalkyl, haloalkoxy, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₁-C₆alkoxyalkyl, optionally substituted C₁-C₆ carboxyalkyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminoalkyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl,optionally substituted aryl C₁-C₆ alkyl, optionally substituted aryloxy,optionally substituted heterocycloalkyl, or optionally substitutedheteroaryl.
 44. The method of claim 43 where the disease is cancer. 45.The method of claim 43 where the cancer is breast cancer, colon cancer,rectal cancer, endometrial cancer, gastric carcinoma, glioblastoma,hepatocellular carcinoma, small cell lung cancer, non-small cell lungcancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer,prostate carcinoma, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), or thyroid carcinoma.
 46. The method ofclaim 43 where the cancer is ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, or glioblastomas.